Prostaglandin endoperoxide H synthase biosynthesis inhibitors

ABSTRACT

The present invention describes pyridazinone compounds of formula I 
     
       
         
         
             
             
         
       
     
     which are cyclooxygenase (COX) inhibitors, and in particular, are selective inhibitors of cyclooxygenase-2 (COX-2). COX-2 is the inducible isoform associated with inflammation, as opposed to the constitutive isoform, cyclooxygenase-1 (COX-1) which is an important “housekeeping” enzyme in many tissues, including the gastrointestinal (GI) tract and the kidneys. The selectivity of these compounds for COX-2 minimizes the unwanted GI and renal side-effects seen with currently marketed non-steroidal anti-inflammatory drugs (NSAIDs).

This application is a divisional application of U.S. Ser. No. 09/427,768filed Oct. 27, 1999 which is a continuation-in-part application of U.S.Ser. No. 09/261,872 filed Mar. 3, 1999 which is a continuation-in-partof U.S. Ser. No. 09/179,605 filed Oct. 27, 1998 which is acontinuation-in-part application of U.S. Ser. No. 09/129,570 filed Aug.5, 1998, is based in-part on provisional application 60/056,733 filedAug. 22, 1997.

TECHNICAL FIELD

The present invention encompasses novel pyridazinone compounds useful inthe treatment of cyclooxygenase-2 mediated diseases. More particularly,this invention concerns a method of inhibiting prostaglandinbiosynthesis, particularly the induced prostaglandin endoperoxide Hsynthase (PGHS-2, cyclooxygenase-2, COX-2) protein.

BACKGROUND OF THE INVENTION

The prostaglandins are extremely potent substances which produce a widevariety of biological effects, often in the nanomolar to picomolarconcentration range. The discovery of two forms of prostaglandinendoperoxide H synthase, isoenzymes PGHS-1 and PGHS-2, that catalyze theoxidation of arachidonic acid leading to prostaglandin biosynthesis hasresulted in renewed research to delineate the role of these two isozymesin physiology and pathophysiology. These isozymes have been shown tohave different gene regulation and represent distinctly differentprostaglandin biosynthesis pathways. The PGHS-1 pathway is expressedconstitutively in most cell types. It responds to produce prostaglandinsthat regulate acute events in vascular homeostasis and also has a rolein maintaining normal stomach and renal function. The PGHS-2 pathwayinvolves an induction mechanism which has been linked to inflammation,mitogenesis and ovulation phenomena.

Prostaglandin inhibitors provide therapy for pain, fever, andinflammation, and are useful therapies, for example in the treatment ofrheumatoid arthritis and osteoarthritis. The non-steroidalanti-inflammatory drugs NSAIDs) such as ibuprofen, naproxen andfenamates inhibit both isozymes. Inhibition of the constitutive enzymePGHS-1 results in gastrointestinal side effects including ulcers andbleeding and incidence of renal problems with chronic therapy.Inhibitors of the induced isozyme PGHS-2 may provide anti-inflammatoryactivity without the side effects of PGHS-1 inhibitors.

The problem of side-effects associated with NSAID administration hasnever completely been solved in the past. Enteric coated tablets andco-administration with misoprostol, a prostaglandin derivative, havebeen tried in an attempt to minimize stomach toxicity. It would beadvantageous to provide compounds which are selective inhibitors of theinduced isozyme PGHS-2.

The present invention discloses novel compounds which are selectiveinhibitors of PGHS-2.

SUMMARY OF THE INVENTION

The present invention discloses pyridazinone compounds which areselective inhibitors of cyclooxygenase-2 (COX-2). The compounds of thepresent invention have the formula I:

or a pharmaceutically acceptable salt, ester, or prodrug thereof,wherein

X is selected from the group consisting of O, S, —NR⁴, —NOR^(a), and—NNR^(b)R^(c);

R⁴ is selected from the group consisting of alkenyl, alkyl, aryl,arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl,heterocyclic, and heterocyclic alkyl;

R^(a), R^(b), and R^(c) are independently selected from the groupconsisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl;

R is selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl,alkoxyiminoalkoxy, alkyl, alkylcarbonylalkyl, alkylsulfonylalkyl,alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkyl,arylhaloalkyl, arylhydroxyalkyl, aryloxy, aryloxyhaloalkyl,aryloxyhydroxyalkyl, arylcarbonylalkyl, carboxyalkyl, cyanoalkyl,cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylidenealkyl, haloalkenyl, haloalkoxyhydroxyalkyl, haloalkyl,haloalkynyl, heterocyclic, heterocyclic alkoxy, heterocyclic alkyl,heterocyclic oxy, hydroxyalkyl, hydroxyiminoalkoxy, —(CH₂)_(n)C(O)R⁵,—(CH₂)_(n)CH(OH)R⁵, (CH₂)_(n)C(NOR^(d))R⁵,(CH₂)_(n)CH(NOR^(d))R⁵—(CH₂)_(n)CH(NR^(d)R^(e))R⁵, —R⁶R⁷,—(CH₂)_(n)C≡CR⁷,

—(CH₂)_(n)[CH(CX′₃)]_(m)(CH₂)_(p)R⁷, —(CH₂)_(n)(CX′₂)_(m)(CH₂)_(p)R⁷,and —(CH₂)_(n)(CHX′)_(m)(CH₂)_(p)R⁷;

R⁵ is selected from the group consisting of hydrogen, alkenyl, alkyl,alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl,haloalkyl, haloalkynyl, heterocyclic, and heterocyclic alkyl;

R⁶ is selected from the group consisting of alkenylene, alkylene,halo-substituted alkenylene, and halo-substituted alkylene;

R⁷ is selected from the group consisting of hydrogen, alkenyl, alkyl,alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl,heterocyclic, and heterocyclic alkyl;

R^(d) and R^(e) are independently selected from the group consisting ofhydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl,cycloalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl;

X′ is halogen;

m is an integer from 0-5;

n is an integer from 0-10; and

p is an integer from 0-10; and

R¹, R², and R³ are independently selected from the group consisting ofhydrogen, alkenyl, alkoxyalkyl, alkoxyiminoalkoxy, alkoxyiminoalkyl,alkyl, alkynyl, alkylcarbonylalkoxy, alkylcarbonylamino,alkylcarbonylaminoalkyl, aminoalkoxy, aminoalkylcarbonyloxyalkoxyaminocarbonylalkyl, aryl, arylalkenyl, arylalkyl, arylalkynyl,carboxyalkylcarbonyloxyalkoxy, cyano, cycloalkenyl, cycloalkyl,cycloalkylidenealkyl, haloalkenyloxy, haloalkoxy, haloalkyl, halogen,heterocyclic, hydroxyalkoxy, hydroxyiminoalkoxy, hydroxyiminoalkyl,mercaptoalkoxy, nitro, phosphonatoalkoxy, Y, and W; provided that one ofR¹, R², or R³ must be W, and further provided that only one of R¹, R²,or R³ is W;

W is selected from the group consisting of

X¹ is selected from the group consisting of S(O)₂, S(O)(NR¹⁰), S(O),Se(O)₂, P(O)(OR¹¹), and P(O)(NR¹²R¹³);

X² is selected from the group consisting of hydrogen, alkenyl, alkyl,alkynyl and halogen;

R⁹ is selected from the group consisting of alkenyl, alkoxy, alkyl,alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl,cycloalkyl, dialkylamino, —NHNH₂, and —NCHN(R¹⁰)R¹¹;

R¹⁰, R¹¹, R¹², and R¹³ are independently selected from the groupconsisting of hydrogen, alkyl, and cycloalkyl, or R¹² and R¹³ can betaken together, with the nitrogen to which they are attached, to form a3-6 membered ring containing 1 or 2 heteroatoms selected from the groupconsisting of O, S, and NR⁷;

Y is selected from the group consisting of —OR¹⁴, —SR¹⁴,—C(R¹⁶)(R¹⁷)R¹⁴, —C(O)R¹⁴, —C(O)OR¹⁴, —N(R¹⁶)C(O)R¹⁴, —NC(R¹⁶)R¹⁴, and—N(R¹⁶)R¹⁴;

R¹⁴ is selected from the group consisting of hydrogen, alkenyl,alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl,cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocyclic, heterocyclic alkyl, hydroxyalkyl, and NR¹⁸R¹⁹; and

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently selected from the groupconsisting of hydrogen, alkenyl, alkoxy, alkyl, cycloalkenyl,cycloalkyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl.

DETAILED DESCRIPTION OF THE INVENTION

All patents, patent applications, and literature references cited in thespecification are hereby incorporated by reference in their entirety. Inthe case of inconsistencies, the present disclosure, includingdefinitions, will prevail.

In one embodiment, compounds of the present invention have formula Iwherein,

R² is W;

X¹ is selected from S(O)₂, S(O), Se(O)₂, and S(O)(NR¹⁰);

R⁹ is selected from alkenyl, alkoxy, alkyl, alkylamino,alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, anddialkylamino; and

X, X²R, R¹, R³, and R¹⁰ are as defined in formula I.

In another embodiment, compounds of the present invention have formula Iwherein,

R² is W;

W is

X¹ is selected from S(O)₂, S(O), Se(O)₂, and S(O)(NR¹⁰);

R⁹ is selected from alkenyl, alkoxy, alkyl, alkylamino,alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, anddialkylamino; and

X, X², R, R¹, R³, and R¹⁰ are as defined in formula I.

In another embodiment, compounds of the present invention have formula Iwherein,

R² is W;

W is

X² is selected from hydrogen and halogen;

R is selected from hydrogen, alkenyl, alkyl, alkynyl,alkylcarbonylalkyl, alkylsulfonylalkyl, carboxyalkyl, cyanoalkyl,haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl,arylalkynyl, heterocyclic, heterocyclic alkyl, arylalkyl,—(CH₂)_(n)C(O)R⁵, —(CH₂)_(n)C≡CR⁷, and—(CH₂)_(n)[CH(CX′₃)]_(m)(CH₂)_(p)R⁷;

R¹ and R³ are independently selected from hydrogen, alkenyl,alkoxyalkyl, alkyl, alkynyl, alkylcarbonylamino,alkylcarbonylaminoalkyl, aminocarbonylalkyl, aryl, cyano, cycloalkenyl,cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, halogen,nitro, and Y; and

X, X¹, X′, R⁵, R⁷, R⁹, n, m, p, and Y are as defined in formula I.

In another embodiment, compounds of the present invention have formula Iwherein,

R² is W;

W is

X² is selected from hydrogen and halogen;

R is selected from hydrogen, alkenyl, alkyl, alkynyl,alkylcarbonylalkyl, alkylsulfonylalkyl, carboxyalkyl, cyanoalkyl,haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl,arylalkynyl, heterocyclic, heterocyclic alkyl, arylalkyl, and—(CH₂)_(n)C(O)R⁵;

R¹ and R³ are independently selected from hydrogen, alkenyl,alkoxyalkyl, alkyl, alkynyl, alkylcarbonylamino,alkylcarbonylaminoalkyl, aminocarbonylalkyl, aryl, cyano, cycloalkenyl,cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, halogen,heterocyclic, heterocyclic alkyl, nitro, and Y; and

X, X¹, R⁵, R⁹, n, and Y are as defined in formula I.

In another embodiment, compounds of the present invention have formula Iwherein,

R² is W;

W is

X² is selected from hydrogen and halogen;

R is selected from hydrogen, alkyl, aryl, haloalkyl, heterocyclic,heterocyclic alkyl, and —(CH₂)_(n)C(O)R⁵;

R¹ and R³ are independently selected from hydrogen, alkenyl,alkoxyalkyl, alkyl, alkynyl, alkylcarbonylamino,alkylcarbonylaminoalkyl, aminocarbonylalkyl, aryl, cyano, cycloalkenyl,cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, halogen,heterocyclic, heterocyclic alkyl, nitro, and Y; and

X, X¹, R⁵, R⁹, n, and Y are as defined in formula I.

In another embodiment, compounds of the present invention have formula Iwherein,

R² is W;

W is

X² is selected from hydrogen and halogen;

R is selected from alkyl, aryl, haloalkyl, heterocyclic, heterocyclicalkyl, and arylalkyl wherein the aryl portion is optionally substitutedwith 1, 2, 3, 4, or 5 substituents selected from halogen; and

R¹ is selected from aryl, arylalkyl, heterocyclic, heterocyclic alkyl,hydroxyalkoxy, and Y; and

X, X¹, R³, R⁹, and Y are as defined in formula I.

In another embodiment, compounds of the present invention have formula Iwherein,

R² is W;

W is

X² is selected hydrogen and halogen;

R is selected from the group consisting of alkyl, aryl, haloalkyl,heterocyclic, heterocyclic alkyl and arylalkyl wherein the aryl portionis optionally substituted with 1, 2, 3, 4, or 5 substituents selectedfrom halogen;

R¹ is selected from the group consisting of aryl, arylalkyl,heterocyclic, heterocyclic alkyl, hydroxyalkoxy, and Y;

Y is —OR¹⁴;

R¹⁴ is selected from the group consisting of alkenyl, alkyl, and aryl;

R³ is hydrogen; and

X, X¹, and R⁹ are as defined in formula I.

In another embodiment, compounds of the present invention have formula Iwherein,

R² is W;

W is

X¹ is S(O)₂;

X² is selected from hydrogen and halogen;

R is selected from aryl, haloalkyl, heterocyclic, heterocyclic alkyl andarylalkyl wherein the aryl portion is optionally substituted with 1, 2,3, 4, or 5 substituents selected from halogen;

R¹ is aryl optionally substituted with 1, 2, or 3 substituentsindependently selected from chlorine and fluorine;

R³ is hydrogen; and

X and R⁹ are as defined in formula I.

In another embodiment, compounds of the present invention have formula Iwherein,

R² is W;

W is

X is O;

X¹ is S(O)₂;

R⁹ is selected from the group consisting of alkyl and amino;

X² is selected from hydrogen and halogen;

R is selected from alkenyl, alkyl, alkynyl, aryl, arylalkyl, andhaloalkyl;

R¹ is selected from alkyl, aryl, arylalkyl, haloalkoxy, hydroxyalkoxy,and Y;

Y is —OR¹⁴;

R¹⁴ is selected from alkenyl, alkyl, and aryl; and

R³ is hydrogen.

In another embodiment, compounds of the present invention have formula Iwherein,

R² is W;

W is

X¹ is S(O)₂;

R⁹ is selected from alkyl and amino;

X² is selected from hydrogen and fluorine;

R is selected from haloalkyl, aryl, and alkyl;

R¹ is selected from isobutyloxy, isopentyloxy,1-(3-methyl-3-butenyl)oxy, 2-hydroxy-2-methyl-propyloxy,3-hydroxy-3-methylbutoxy, neopentyloxy, isopentyl, aryloxy,4-fluorophenoxy, and aryl optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofchlorine and fluorine;

R³ is hydrogen; and

X is as defined in formula I.

In another embodiment, compounds of the present invention have formula Iwherein,

R² is W;

-   -   W is

X is O;

X¹ is selected from S(O)₂ and S(O)(NR¹⁰);

R⁹ is alkyl;

X² is selected from hydrogen and fluorine;

R is selected from alkenyl, alkyl alkynyl, aryl, arylalkyl andhaloalkyl;

R¹ is selected from alkyl, aryl, hydroxyalkoxy and Y;

Y is —OR¹⁴;

R¹⁴ is selected from alkenyl, alkyl, and aryl;

R³ is hydrogen; and

R¹⁰ is as defined in formula I.

In another embodiment, compounds of the present invention have formula Iwherein,

R² is W;

W is

X is O;

X¹ is S(O)₂;

R⁹ is amino;

X² is selected from hydrogen and fluorine;

R is selected from alkenyl, alkyl, alkynyl, aryl, arylalkyl, andhaloalkyl;

R¹ is selected from alkyl, aryl, hydroxyalkoxy and Y;

Y is —OR¹⁴;

R¹⁴ is selected from alkenyl, alkyl, and aryl; and

R³ is hydrogen.

In another embodiment, compounds of the present invention have formula Iwherein,

R² is W;

W is

X is O;

X¹ is SO₂;

R⁹ is methyl;

X² is hydrogen;

R is selected from t-butyl, 3-chlorophenyl, 3,4-difluorophenyl,4-fluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, and2,2,2-trifluoroethyl;

R¹ is selected from isobutoxy, isopentyloxy, (3-methyl-3-butenyl)oxy,2-hydroxy-2-methyl-propoxy, 3-hydroxy-3-methylbutoxy, neopentyloxy,isopentyl, 4-fluorophenyl, 4-chlorophenyl, 4-chloro-3-fluoro-phenyl,4-fluorophenoxy and Y;

Y is —OR¹⁴;

R¹⁴ is aryl; and

R³ is hydrogen.

In another embodiment, compounds of the present invention have formula Iwherein,

R² is W;

W is

X is O;

X¹ is S(O)₂;

R⁹ is amino;

X² is hydrogen;

R is selected from t-butyl, 3-chlorophenyl, 3,4-difluorophenyl,4-fluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, and2,2,2-trifluoroethyl;

R¹ is selected consisting of isobutoxy, isopentyloxy,(3-methyl-3-butenyl)oxy, 2-hydroxy-2-methyl-propoxy,3-hydroxy-3-methylbutoxy, neopentyloxy, isopentyl, 4-fluorophenyl,4-chlorophenyl, 4-chloro-3-fluoro-phenyl, 4-fluorophenoxy, and Y;

Y is —OR¹⁴;

R¹⁴ is aryl; and

R³ is hydrogen.

Another embodiment of the present invention relates to pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof formula I or a pharmaceutically acceptable salt, ester, amide, orprodrug thereof in combination with a pharmaceutically acceptablecarrier for inhibiting prostaglandin biosynthesis.

Another embodiment of the invention relates to a method of inhibitingprostaglandin biosynthesis comprising administering a therapeuticallyeffective amount of a compound of formula I or a pharmaceuticallyacceptable salt, ester, amide, or prodrug thereof.

Another embodiment of the invention relates to a method of treatingpain, fever, inflammation, rheumatoid arthritis, osteoarthritis,adhesions, and cancer comprising administering a therapeuticallyeffective amount of a compound of formula I or a pharmaceuticallyacceptable salt, ester, amide, or prodrug thereof.

Another embodiment of the present invention relates to a method ofpreparing a compound of formula I wherein,

R² is W;

W is comprising the step of treating a compound of formula I wherein Ris hydrogen with an alkylating agent, wherein the alkylating agent hasthe formula R⁹⁹-Q wherein Q is a leaving group and R⁹⁹ is selected fromthe group consisting of 1,1,1-trifluoroethyl, 3-(2-methyl)propenyl,4-(2-methyl)but-2-enyl, 1,1-dichloropropen-3-yl,2,3,3,4,4,4-hexafluorobuten-1-yl, propargyl, phenylpropargyl, phenyl,benzyl, α-methyl-4-fluorobenzyl, 2,3,4,5,6-pentafluorobenzyl,4-fluorobenzyl, 4-fluorophenyl, 2,4-difluorobenzyl, 3-thienylmethyl,5-methylthien-2-ylmethyl, 5-chlorothien-2-ylmethyl, and2-benzo[b]thienylmethyl.

Another embodiment of the present invention relates to a method ofpreparing a compound of formula I wherein,

R² is W;

W is

X, X¹, X², R, R¹, R², and R³ are as defined in formula I; comprising thestep of treating a compound of formula I wherein R is hydrogen with analkylating agent, wherein the alkylating agent has the formula R⁹⁹-Qwherein Q is a leaving group and R⁹⁹ is selected from the groupconsisting of 1,1,1-trifluoroethyl, phenyl, benzyl,α-methyl-4-fluorobenzyl, 4-fluorobenzyl, 4-fluorophenyl, and2,4-difluorobenzyl.

Another embodiment of the present invention relates to a method ofpreparing a compound of formula I wherein,

R² is W;

W is

X, X¹, X², R, R¹, R², and R³ are as defined in formula I; comprising thestep of treating a compound of formula I wherein R is hydrogen with analkylating agent, wherein the alkylating agent has the formula R⁹⁹-Qwherein Q is a leaving group and R⁹⁹ is selected from the groupconsisting of 1,1,1-trifluoroethyl, benzyl, and 4-fluorophenyl.

Another embodiment of the present invention relates to a method forregioselectively preparing a 4,5-disubstituted pyridazinone comprisingthe steps of

a) treating a compound of formula IV

wherein R⁹⁸ is an alkyl or aryl group; and X is a leaving group;

with a nucleophilic agent to displace the X group;

b) converting the —OR⁹⁸ to a leaving group; and

c) treating the compound with a second nucleophilic agent to provide the4,5-disubstituted pyridazinone.

Another embodiment of the present invention relates to a method forregioselectively preparing a 4,5-disubstituted pyridazinone comprisingthe steps of

a) treating a compound of formula IV

wherein R⁹⁸ is an alkyl or aryl group; and X is a leaving group;

with a nucleophilic agent to displace the X group;

b) converting the —OR⁹⁸ to a leaving group; and

c) treating the compound with a second nucleophilic agent to provide the4,5-disubstituted pyridazinone wherein the benzyl group is removed usinga Lewis acid.

Another embodiment of the present invention relates to a method forregioselectively preparing a 4,5-disubstituted pyridazinone comprisingthe steps of treating a compound of formula V

wherein

R¹ and R³ are independently selected from the group consisting ofhydrogen, alkenyl, alkoxyalkyl, alkyl, alkynyl, alkylcarbonylamino,alkylcarbonylaminoalkyl, aminoalkoxy, alkylcarbonylalkoxy,aminocarbonylalkyl, aryl, arylalkenyl, arylalkyl, arylalkynyl, cyano,cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylidenealkyl, haloalkenyloxy, haloalkoxy, haloalkyl, halogen,heterocyclic, heterocyclic alkyl, hydroxyalkoxy, hydroxyalkylamino,hydroxyalkylthio, mercaptoalkoxy, nitro, and Y;

Y is selected from the group consisting of —OR¹⁴, —SR¹⁴,—C(R¹⁶)(R¹⁷)R¹⁴, —C(O)R¹⁴, —C(O)OR¹⁴, —N(R¹⁶)C(O)R¹⁴, —NC(R¹⁶)R¹⁴, and—N(R¹⁶)R¹⁴;

R¹⁴ is selected from the group consisting of hydrogen, alkenyl,alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl,cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocyclic, heterocyclic alkyl and NR¹⁸R¹⁹; and

R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently selected from the groupconsisting of hydrogen, alkenyl, alkoxy, alkyl, cycloalkenyl,cycloalkyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl;

X¹ is selected from the group consisting of S(O)₂, S(O)(NR¹⁰), S(O),Se(O)₂, P(O)(OR¹¹), and P(O)(NR¹²R¹³);

R⁹ is selected from the group consisting of alkenyl, alkoxy, alkyl,alkynyl, amino, cycloalkenyl, cycloalkyl, dialkylamino, —NHNH₂, and—NCHN(R¹⁰)R¹¹; and

R¹⁰, R¹¹, R¹², and R¹³ are independently selected from the groupconsisting of hydrogen, alkyl, and cycloalkyl, or R¹² and R¹³ can betaken together, with the nitrogen to which they are attached, to form a3-6 membered ring containing 1 or 2 heteroatoms selected from the groupconsisting of O, S, and NR⁷;

R⁷ is selected from the group consisting of hydrogen, alkenyl, alkyl,alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl,heterocyclic, and heterocyclic alkyl;

with a hydrazine having the formula RNHNH₂ wherein R is selected fromthe group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl,alkylcarbonylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl,arylalkoxy, arylalkyl, arylalkynyl, arylhaloalkyl, arylhydroxyalkyl,aryloxy, aryloxyhaloalkyl, aryloxyhydroxyalkyl, arylcarbonylalkyl,carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl,cycloalkylalkyl, haloalkenyl, haloalkoxyhydroxyalkyl, haloalkyl,haloalkynyl, heterocyclic, heterocyclic alkoxy, heterocyclic alkyl,heterocyclic oxy, hydroxyalkyl, —(CH₂)_(n)C(O)R⁵, —(CH₂)_(n)CH(OH)R⁵,—(CH₂)_(n)C(NOR^(d))R⁵, —(CH₂)_(n)CH(NOR^(d))R⁵,—(CH₂)_(n)CH(NR^(d)R^(e))R⁵, —R⁶R⁷, —(CH₂)_(n)C≡CR⁷,—(CH₂)_(n)[CH(CX′₃)]_(m)(CH₂)_(n)R⁷—(CH₂)_(n)(CX′₂)_(m)(CH₂)_(n)R⁷, and—(CH₂)_(n)(CHX′)_(m)(CH₂)_(n)R⁷;

R⁵ is selected from the group consisting of alkenyl, alkyl, alkynyl,aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl, haloalkyl,haloalkynyl, heterocyclic, and heterocyclic alkyl;

R⁶ is selected from the group consisting of alkenylene, alkylene,halo-substituted alkenylene, and halo-substituted alkylene;

R⁷ is selected from the group consisting of hydrogen, alkenyl, alkyl,alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl,heterocyclic, and heterocyclic alkyl;

R^(d) and R^(e) are independently selected from the group consisting ofhydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl,cycloalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl;

X′ is halogen;

n is an integer from 0-10;

m is an integer from 0-5;

to furnish the pyridazinone of formula III

wherein X¹, R, R¹, R³, and R⁹ are as previously defined;

X is selected from the group consisting of O, S, —NR⁴, —NOR^(a), and—NNR^(b)R^(c);

R⁴ is selected from the group consisting of alkenyl, alkyl, aryl,arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl,heterocyclic, and heterocyclic alkyl;

R^(a), R^(b), and R^(c) are independently selected from the groupconsisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl;and

X² is selected from the group consisting of hydrogen, alkenyl, alkyl,alkynyl and halogen.

A preferred embodiment of the present invention relates to a compound offormula VI

or a pharmaceutically acceptable salt, ester, or prodrug thereof,wherein

R is selected from alkyl, aryl, arylalkyl, haloalkyl, and haloalkenyl;

R¹ is selected from alkoxy, aminoalkylcarbonyloxyalkoxy,carboxyalkylcarbonyloxyalkoxy, hydroxyalkyl, hydroxyalkoxy, andphosphonatoalkoxy,

R⁹ is selected from alkyl, alkylcarbonylamino, and amino.

Another preferred embodiment of the present invention relates to acompound of formula VI wherein,

R is aryl;

R¹ is hydroxyalkoxy; and

R⁹ is selected from alkyl and amino.

Another preferred embodiment of the present invention relates to acompound of formula VI wherein,

R is aryl;

R¹ is hydroxyalkoxy; and

R⁹ is methyl.

Another preferred embodiment of the present invention relates to acompound of formula VI wherein,

R is phenyl optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halogen and haloalkyl;

R¹ is hydroxyalkoxy; and

R⁹ is selected from alkyl and amino.

Another preferred embodiment of the present invention relates to acompound of formula VI wherein,

R is phenyl optionally substituted with 1 or 2 substituentsindependently selected from chlorine and fluorine;

R¹ is hydroxyalkoxy; and

R⁹ is selected from alkyl and amino.

Another preferred embodiment of the present invention relates to acompound of formula VI wherein,

R is haloalkyl; and

R¹ is hydroxyalkoxy; and

R⁹ is selected from alkyl and amino.

Another preferred embodiment of the present invention relates to acompound of formula VI wherein,

R is phenyl optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from halogen and haloalkyl;

R¹ is aminoalkylcarbonyloxyalkoxy; and

R⁹ is selected from alkyl and amino.

Another preferred embodiment of the present invention relates to acompound of formula VI wherein,

R is phenyl optionally substituted with 1, 2, 3, 4, or 5 substituentseach independently selected from halogen and haloalkyl;

R¹ is carboxyalkylcarbonyloxyalkoxy; and

R⁹ is selected from alkyl and amino.

Another preferred embodiment of the present invention relates to acompound of formula VI wherein,

R is phenyl optionally substituted with 1, 2, 3, 4, or 5 substituentseach independently selected from halogen and haloalkyl;

R¹ is phosphonatoalkoxy; and

R⁹ is selected from alkyl and amino.

Another preferred embodiment of the present invention relates to acompound of formula VI wherein,

R is phenyl optionally substituted with 1, 2, 3, 4, or 5 substituentseach independently selected from halogen and haloalkyl;

R¹ is hydroxyalkoxy; and

R⁹ is alkylcarbonylamino.

Another preferred embodiment of the present invention relates to acompound of formula VI wherein,

R is selected from haloalkyl and phenyl optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from halogen andhaloalkyl;

R¹ is alkoxy; and

R⁹ is selected from the group consisting of alkyl, alkylcarbonylamino,and amino.

Another preferred embodiment of the present invention relates to acompound of formula VI wherein,

R is tert-butyl;

R¹ is selected from the group consisting of aminoalkylcarbonyloxyalkoxy,carboxyalkylcarbonyloxyalkoxy, hydroxyalkoxy, and phosphonatoalkoxy; and

R⁹ is selected from the group consisting of alkyl, alkylcarbonylamino,and amino.

Another preferred embodiment of the present invention relates to2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneor a pharmaceutically acceptable salt, ester, or prodrug thereof.

DEFINITIONS OF TERMS

As used throughout this specification and the appended claims, thefollowing terms have the following meanings:

The term “alkenyl,” as used herein, refers to a straight or branchedchain hydrocarbon containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond formed by the removal of twohydrogens. Representative examples of alkenyl include, but are notlimited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl andthe like.

The term “alkenylene,” denotes a divalent group derived from a straightor branched chain hydrocarbon of from 2 to 10 carbon atoms containing atleast one double bond. Representative examples of alkenylene include,but are not limited to, —CH═CH—, —CH═CH₂CH₂—, —CH═C(CH₃)CH₂—, and thelike.

The term “alkoxy,” as used herein, refers to an alkyl group, as definedherein, appended to the parent molecular moiety through an oxy moiety,as defined herein. Representative examples of alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy and the like.

The term “alkoxyalkoxy,” as used herein, refers to an alkoxy group, asdefined herein, appended to the parent molecular moiety through anotheralkoxy group, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy,2-methoxyethoxy, methoxymethoxy, and the like.

The term “alkoxyalkoxyalkyl,” as used herein, refers to an alkoxyalkoxygroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofalkoxyalkoxyalkyl include, but are not limited to,tert-butoxymethoxymethyl, ethoxymethoxymethyl, (2-methoxyethoxy)methyl,2-(2-methoxyethoxy)ethyl, and the like.

The term “alkoxyalkyl,” as used herein, refers to an alkoxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of alkoxyalkylinclude, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl,2-methoxyethyl, methoxymethyl, and the like.

The term “alkoxyalkylcarbonyl,” as used herein, refers to an alkoxyalkylgroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples ofalkoxyalkylcarbonyl include, but are not limited to,tert-butoxymethylcarbonyl, 2-ethoxyethylcarbonyl,2-methoxyethylcarbonyl, methoxymethylcarbonyl, and the like.

The term “alkoxycarbonyl,” as used herein, refers to an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl, and the like.

The term “alkoxycarbonylalkenyl,” as used herein, refers to analkoxycarbonyl group, as defined herein, appended to the parentmolecular moiety through an alkenyl group, as defined herein.Representative examples of alkoxycarbonylalkenyl include, but are notlimited to, 3-methoxycarbonyl-1-propenyl, 4-ethoxycarbonyl-2-butenyl,and the like.

The term “alkoxycarbonylalkyl,” as used herein, refers to analkoxycarbonyl group, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.Representative examples of alkoxycarbonylalkyl include, but are notlimited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl,2-tert-butoxycarbonylethyl, and the like.

The term “alkoxycarbonylalkylthio,” as used herein, refers to analkoxycarbonylalkyl group, as defined herein, appended to the parentmolecular moiety through a thio moiety, as defined herein.Representative examples of alkoxycarbonylalkylthio include, but are notlimited to, 3-methoxycarbonylpropylsulfanyl,4-ethoxycarbonylbutylsulfanyl, and the like.

The term “alkoxyimino,” refers to a R₈₅ON=group wherein R₈₅ is alkyl, asdefined herein.

The term “alkoxyiminoalkoxy,” as used herein, refers to an alkoxyiminogroup, as defined herein, appended to the parent molecular moietythrough an alkoxy group, as defined herein. Representative examples ofalkoxyiminoalkoxy include, but are not limited to,2-(methoxyimino)ethoxy, 2-(ethoxyimino)-1-propoxy,3-(isopropoxyimino)-1-butoxy, and the like.

The term “alkoxyiminoalkyl,” as used herein, refers to an alkoxyiminogroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofalkoxyiminoalkyl include, but are not limited to, 2-(methoxyimino)ethyl,2-(ethoxyimino)-1-propyl, 3-(isopropoxyimino)-1-butyl, and the like.

The term “alkyl,” as used herein, refers to a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,n-decyl, and the like.

The term “alkylamino,” as used herein, refers to an alkyl group, asdefined herein, appended to the parent molecular moiety through an aminogroup, as defined herein. Representative examples of alkylamino include,but are not limited to, methylamino, ethylamino, propylamino, and thelike.

The term “alkylaminosulfonyl,” as used herein, refers to an alkylaminogroup, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples ofalkylaminosulfonyl include, but are not limited to, methylaminosulfonyl,ethylaminosulfonyl, propylaminosulfonyl, and the like.

The term “alkylcarbonyl,” as used herein, refers to an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, 1-oxopentyl, and the like.

The term “alkylcarbonylalkoxy,” as used herein, refers to analkylcarbonyl group, as defined herein, appended to the parent molecularmoiety through an alkoxy group, as defined herein. Representativeexamples of alkylcarbonylalkoxy include, but are not limited to,2-oxopropoxy, 3,3-dimethyl-2-oxopropoxy, 3-oxobutoxy, 3-oxobutoxy,3-oxopentyloxy, and the like.

The term “alkylcarbonylalkyl,” as used herein, refers to analkylcarbonyl group, as defined herein, appended to the parent molecularmoiety through an alkyl group, as defined herein. Representativeexamples of alkylcarbonylalkyl include, but are not limited to,2-oxopropyl, 3,3-dimethyl-2-oxopropyl; 3-oxobutyl, 3-oxopentyl, and thelike.

The term “alkylcarbonylamino,” as used herein, refers to analkylcarbonyl group, as defined herein, appended to the parent molecularmoiety through an amino group, as defined herein. Representativeexamples of alkylcarbonylamino include, but are not limited to,acetylamino, 1-oxopropylamino, 2,2-dimethyl-1-oxopropylamino, and thelike.

The term “alkylcarbonylaminoalkyl,” as used herein, refers to analkylcarbonylamino group, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.Representative examples of alkylcarbonylaminoalkyl include, but are notlimited to, acetylaminomethyl, 2-(1-oxopropylamino)ethyl, and the like.

The term “alkylcarbonyloxy,” as used herein, refers to an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an oxy moiety, as defined herein. Representative examples ofalkylcarbonyloxy include, but are not limited to, acetyloxy,ethylcarbonyloxy, tert-butylcarbonyloxy, and the like.

The term “alkylene,” denotes a divalent group derived from a straight orbranched chain hydrocarbon of from 1 to 10 carbon atoms. Representativeexamples of alkylene include, but are not limited to, —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂—, and the like.

The term “alkylimino,” as used herein, refers to R₈₁N=group, wherein R₈₁is alkyl, as defined herein.

The term “alkylsulfinyl,” as used herein, refers to an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfinyl group, as defined herein. Representative examples ofalkylsulfinyl include, but are not limited, methylsulfinyl,ethylsulfinyl, and the like.

The term “alkylsulfinylalkyl,” as used herein, refers to analkylsulfinyl group, as defined herein, appended to the parent molecularmoiety through an alkyl group, as defined herein. Representativeexamples of alkylsulfinylalkyl include, but are not limited,methylsulfinylmethyl, ethylsulfinylmethyl, and the like

The term “alkylsulfonyl,” as used herein, refers to an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited, methylsulfonyl,ethylsulfonyl, and the like.

The term “alkylsulfonylalkyl,” as used herein, refers to analkylsulfonyl group, as defined herein, appended to the parent molecularmoiety through an alkyl group, as defined herein. Representativeexamples of alkylsulfonylalkyl include, but are not limited,methylsulfonylmethyl, 2-(ethylsulfonyl)ethyl, and the like.

The term “alkylsulfonylamino,” as used herein, refers to analkylsulfonyl group, as defined herein, appended to the parent molecularmoiety through an amino group, as defined herein. Representativeexamples of alkylsulfonylamino include, but are not limited,methylsulfonylamino, ethylsulfonylamino, and the like.

The term “alkylthio,” as used herein, refers to an alkyl group, asdefined herein, appended to the parent molecular moiety through a thiomoiety, as defined herein. Representative examples of alkylthio include,but are not limited, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl,hexylsulfanyl, and the like.

The term “alkylthioalkyl,” as used herein, refers to an alkylthio group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples ofalkylthioalkyl include, but are not limited, methylsulfanylmethyl,2-(ethylsulfanyl)ethyl, and the like.

The term “alkylthioalkylcarbonyl,” as used herein, refers to analkylthioalkyl group, as defined herein, appended to the parentmolecular moiety through a carbonyl group, as defined herein.Representative examples of alkylthioalkylcarbonyl include, but are notlimited, methylsulfanylmethylcarbonyl, 2-(ethylsulfanyl)ethylcarbonyl,and the like.

The term “alkynyl,” as used herein, refers to a straight or branchedchain hydrocarbon group containing from 2 to 10 carbon atoms andcontaining at least one carbon-carbon triple bond. Representativeexamples of alkynyl include, but are not limited, to acetylenyl,1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.

The term “alkynylene,” denotes a divalent group derived from a straightor branched chain hydrocarbon of from 2 to 10 carbon atoms containing atleast one triple bond. Representative examples of alkynylene include,but are not limited to, —C≡C—, —CH₂C≡C—, —CH(CH₃)CH₂C≡C—, —C≡CCH₂—,—C≡CCH(CH₃)CH₂—, and the like.

The term “amino,” as used herein, refers to a —NH₂ group.

The term “aminoalkoxy,” as used herein, refers to an amino group, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of aminoalkoxyinclude, but are not limited to, 2-aminomethoxy, 3-aminopropoxy,4-amino-1-methylhexyloxy, and the like.

The term “aminoalkyl,” as used herein, refers to an amino group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of aminoalkyl include,but are not limited to, aminomethyl, 2-aminoethyl, 3-aminopropyl,4-amino-1-methylhexyl, and the like.

The term “aminoalkylcarbonyl,” as used herein, refers to an aminoalkylgroup, as defined herein, appended to the parent molecular moietythrough an carbonyl group, as defined herein. Representative examples ofaminoalkylcarbonyl include, but are not limited to, 2-amino-1-oxoethyl(2-aminoacetyl), 3-amino-1-oxopropyl, and the like.

The term “aminoalkylcarbonyloxy,” as used herein, refers to anaminoalkylcarbonyl group, as defined herein, appended to the parentmolecular moiety through an oxy moiety, as defined herein.Representative examples of aminoalkylcarbonyloxy include, but are notlimited to, 2-amino-1-oxoethyloxy (2-aminoacetoxy),3-amino-1-oxopropyloxy, and the like.

The term “aminoalkylcarbonyloxyalkoxy,” as used herein, refers to anaminoalkylcarbonyloxy group, as defined herein, appended to the parentmolecular moiety through an alkoxy group, as defined herein.Representative examples of aminoalkylcarbonyloxyalkoxy include, but arenot limited to, 2-(2-amino-1-oxoethyloxy)ethoxy,4-(3-amino-1-oxopropyloxy)butoxy,3-(3-amino-1-oxopropyloxy)-3-methyl-1-butoxy,3-(2-amino-1-oxoethyloxy)-3-methyl-1-butoxy and the like.

The term “aminocarbonyl,” as used herein, refers to a H₂NC(O)— group.

The term “aminocarbonylalkoxy,” as used herein, refers to anaminocarbonyl group, as defined herein, appended to the parent molecularmoiety through an alkoxy group, as defined herein. Representativeexamples of aminocarbonylalkoxy include, but are not limited to,2-(aminocarbonyl)ethoxy, 3-(aminocarbonyl)propoxy, and the like.

The term “aminocarbonylalkyl,” as used herein, refers to anaminocarbonyl group, as defined herein, appended to the parent molecularmoiety through an alkyl group, as defined herein. Representativeexamples of aminocarbonylalkyl include, but are not limited to,2-(aminocarbonyl)ethyl, 3-(aminocarbonyl)propyl, and the like.

The term “aminosulfonyl,” as used herein, refers to H₂NS(O)₂— group.

The term “aryl,” as used herein, refers to a monocyclic-ring system, ora bicyclic- or a tricyclic fused ring system wherein one or more of thefused rings are aromatic. Representative examples of aryl include, butare not limited to, azulenyl, indanyl, indenyl, naphthyl, phenyl,tetrahydronaphthyl, and the like.

The aryl groups of this invention can be substituted with 1, 2, or 3substituents independently selected from alkenyl, alkenyloxy, alkoxy,alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxyalkylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkenyl, alkoxycarbonylalkyl,alkoxycarbonylalkylthio, alkyl, alkylamino, alkylaminosulfonyl,alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonylamino, alkylcarbonyloxy,alkylimino, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl,alkylsulfonylalkyl, alkylsulfonylamino, alkylthio, alkylthioalkyl,alkylthioalkylcarbonyl, alkynyl, amino, aminocarbonyl,aminocarbonylalkoxy, aminosulfonyl, aryl, arylalkoxy, arylalkyl,aryloxy, arylcarbonyl, carboxy, carboxyalkenyl, carboxyalkoxy,carboxyalkyl, cyano, cyanoalkoxy, cyanoalkyl, cycloalkyl, dialkylamino,dialkylaminosulfonyl, ethylenedioxy, formyl, formylalkyl, halogen,haloalkoxy, haloalkyl, heterocyclic, heterocyclic alkoxy, heterocyclicalkyl, heterocyclic carbonyl, hydroxy, hydroxyalkoxy, hydroxyalkyl,methylenedioxy, mercapto, nitro, and sulfo. Representative examples ofsubstituted aryl include, but are not limited to, 3-chlorophenyl,3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl,3-chloro-4-fluoro-phenyl, 3,4,-difluorophenyl, 4-methylsulfonylphenyl,4-aminosulfonylphenyl, pentafluorophenyl, and the like.

The term “arylalkenyl,” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through analkenyl group, as defined herein. Representative examples of arylalkenylinclude, but are not limited to, 3-phenylpropen-2-yl,3-phenylpropen-3-yl, 2-naphth-2-ylbuten-4-yl, and the like.

The term “arylalkoxy,” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of arylalkoxyinclude, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy,5-phenylpentyloxy, and the like.

The term “arylalkoxycarbonyl,” as used herein, refers to an arylalkoxygroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples ofarylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl,naphth-2-ylmethoxycarbonyl, and the like.

The term “arylalkyl,” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of arylalkyl include,but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl,2-naphth-2-ylethyl, and the like.

The term “arylalkylthio,” as used herein, refers to an arylalkyl group,as defined herein, appended to the parent molecular moiety through athio moiety, as defined herein. Representative examples of arylalkylthioinclude, but are not limited to, 2-phenylethylsulfanyl,3-naphth-2-ylpropylsulfanyl, 5-phenylpentylsulfanyl and the like.

The term “arylalkynyl,” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through analynyl group, as defined herein. Representative examples of arylalkynylinclude, but are not limited to, 3-phenylpropyn-2-yl,3-phenylpropyn-3-yl, 2-naphth-2-ylbutyn-4-yl, and the like.

The term “arylcarbonyl,” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofarylcarbonyl include, but are not limited to, benzoyl, naphthoyl, andthe like.

The term “arylcarbonylalkyl,” as used herein, refers to an arylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofarylcarbonylalkyl include, but are not limited to, 3-benzylpropyl,3-naphthylpropyl, and the like.

The term “arylhaloalkyl,” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through ahaloalkyl group, as defined herein. Representative examples ofarylhaloalkyl include, but are not limited to,1,1-difluoro-3-phenylpropyl, 1,1-dibromo-3-phenylpropyl,1,1-difluoro-2-naphth-2-ylethyl, and the like.

The term “arylhydroxyalkyl,” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through ahydroxyalkyl group, as defined herein. Representative examples ofarylhydroxyalkyl include, but are not limited to,1-hydroxy-3-phenylpropyl, 2-hydroxy-3-phenylpropyl,1-hydroxy-2-naphth-2-ylethyl, and the like.

The term “aryloxy,” as used herein, refers to an aryl group, as definedherein, appended to the parent molecular moiety through an oxy moiety,as defined herein. Representative examples of aryloxy include, but arenot limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy,4-methylphenoxy, 3,5-dimethoxyphenoxy, and the like.

The term “aryloxyalkyl,” as used herein, refers to an aryloxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of aryloxyalkylinclude, but are not limited to, 2-phenoxyethyl, 3-naphth-2-yloxypropyl,3-bromophenoxymethyl, and the like.

The term “aryloxyhaloalkyl,” as used herein, refers to an aryloxy group,as defined herein, appended to the parent molecular moiety through ahaloalkyl group, as defined herein. Representative examples ofaryloxyhaloalkyl include, but are not limited to,1,1-difluoro-3-(naphth-2-yloxy)propyl,1,1-difluoro-3-(4-bromophenoxy)butyl, and the like.

The term “aryloxyhydroxyalkyl,” as used herein, refers to an aryloxygroup, as defined herein, appended to the parent molecular moietythrough a hydroxyalkyl group, as defined herein. Representative examplesof aryloxyhydroxyalkyl include, but are not limited to,1-hydroxy-3-(naphth-2-yloxy)propyl, 1-hydroxy-3-(4-bromophenoxy)butyl,and the like.

The term “arylthio,” as used herein, refers to an aryl group, as definedherein, appended to the parent molecular moiety through a thio moiety,as defined herein. Representative examples of arylthio include, but arenot limited to, phenylsulfanyl, naphth-2-ylsulfanyl,5-phenylhexylsulfanyl, and the like.

The term “arylthioalkyl,” as used herein, refers to an arylthio group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of arylthioalkylinclude, but are not limited to, phenylsulfanylmethyl,2-naphth-2-ylsulfanylethyl, 5-phenylhexylsulfanylmethyl, and the like.

The term “azido,” as used herein, refers to a —N₃ group.

The term “carbonyl,” as used herein, refers to a —C(O)— group.

The term “carboxy,” as used herein, refers to a —CO₂H group.

The term “carboxyalkenyl,” as used herein, refers to a carboxy group, asdefined herein, appended to the parent molecular moiety through analkenyl group, as defined herein. Representative examples ofcarboxyalkenyl include, but are not limited to, 3-carboxy-1-propenyl,4-carboxy-1-butenyl, and the like.

The term “carboxyalkoxy,” as used herein, refers to a carboxy group, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples ofcarboxyalkoxy include, but are not limited to, 3-carboxypropoxy,4-carboxybutoxy, and the like.

The term “carboxyalkyl,” as used herein, refers to a carboxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. The alkyl portion of carboxyalkyl may contain1 or 2 hydroxy groups, as defined herein. Representative examples ofcarboxyalkyl include, but are not limited to, carboxymethyl,2-carboxyethyl, 1-hydroxy-3-carboxypropyl, 1,2-dihydroxy-3-carboxypropyland the like.

The term “carboxyalkylcarbonyl,” as used herein, refers to acarboxyalkyl group, as defined herein, appended to the parent molecularmoiety through a carbonyl group, as defined herein. Representativeexamples of carboxyalkylcarbonyl include, but are not limited to,2-carboxy-1-oxoethyl, 3-carboxy-2,3-dihydroxy-1-oxopropyl,3-carboxy-1-oxopropyl, and the like.

The term “carboxyalkylcarbonyloxy,” as used herein, refers to acarboxyalkylcarbonyl group, as defined herein, appended to the parentmolecular moiety through an oxy moiety, as defined herein.Representative examples of carboxyalkylcarbonyloxy include, but are notlimited to, 2-carboxy-1-oxoethoxy, 3-carboxy-2,3-dihydroxy-1-oxopropoxy,3-carboxy-1-oxopropoxy, and the like.

The term “carboxyalkylcarbonyloxyalkoxy,” as used herein, refers to acarboxyalkylcarbonyloxy group, as defined herein, appended to the parentmolecular moiety through an alkoxy group, as defined herein.Representative examples of carboxyalkylcarbonyloxyalkoxy include, butare not limited to, 2-(2-carboxy-1-oxoethoxy)ethoxy,3-(3-carboxy-2,3-dihydroxy-1-oxopropoxy)-3-methylbutoxy,3-(3-carboxy-1-oxopropoxy)-2-methyl-1-propoxy, and the like.

The term “cyano,” as used herein, refers to a —CN group.

The term “cyanoalkoxy,” as used herein, refers to a cyano group, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of cyanoalkoxyinclude, but are not limited to, 2-cyanoethoxy, 3-cyanopropoxy, and thelike.

The term “cyanoalkyl,” as used herein, refers to a cyano group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of cyanoalkyl include,but are not limited to, cyanomethyl; 2-cyanoethyl, 3-cyanopropyl, andthe like.

The term “cycloalkenyl,” as used herein, refers to a cyclalkyl group, asdefined herein, containing one double bond. Representative examples ofcycloalkenyl include, but are not limited to, cyclopentenyl,cyclohexenyl, cycloheptenyl, and the like.

The cycloalkenyl groups of this invention can be substituted with 1, 2,or 3 substituents selected from alkoxy, alkoxyalkoxy, alkoxycarbonyl,alkyl, alkylamino, alkylimino, alkylthio, amino, aminocarbonyl, aryl,arylalkyl, carboxy, cyano, cycloalkyl, dialkylamino, formyl, halogen,haloalkyl, hydroxy, oxo, mercapto, and nitro.

The term “cycloalkenylalkyl,” as used herein, refers to cycloalkenylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofcycloalkenylalkyl include, but are not limited to, cyclopentenylmethyl,cyclohexenylmethyl, and the like.

The term “cycloalkyl,” as used herein, refers to a saturated cyclichydrocarbon group containing from 3 to 8 carbons. Representativeexamples of cycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl.

The cycloalkyl groups of this invention can be substituted with 1, 2, or3 substituents selected from alkoxy, alkoxyalkoxy, alkoxycarbonyl,alkyl, alkylamino, alkylimino, alkylthio, amino, aminocarbonyl, aryl,arylalkyl, carboxy, cyano, cycloalkyl, dialkylamino, formyl, halogen,haloalkyl, hydroxy, oxo, mercapto, and nitro.

The term “cycloalkylalkyl,” as used herein, refers to cycloalkyl group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples ofcycloalkylalkyl include, but are not limited to, cyclopropylmethyl,2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl,4-cycloheptylbutyl, and the like.

The term “cycloalkylcarbonyl,” as used herein, refers to cycloalkylgroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples ofcycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl,2-cyclobutylcarbonyl, cyclohexylcarbonyl, and the like.

The term “cycloalkylidene,” as used herein, refers to cycloalkyl group,as defined herein, appended to the parent molecular moiety through adouble bond. Representative examples of cycloalkylidene include, but arenot limited to, cyclopropylidene, cyclohexylidene, and the like.

The term “cycloalkylidenealkyl,” as used herein, refers tocycloalkylidene group, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.Representative examples of cycloalkylidenealkyl include, but are notlimited to, 2-cyclopropylideneethyl, 3-cyclohexylidenepropyl, and thelike.

The term “dialkylamino,” as used herein, refers to two independent alkylgroups, as defined herein, appended to the parent molecular moietythrough an amino group. Representative examples of dialkylamino include,but are not limited to, diethylamino, dimethylamino, ethylmethylamino,and the like.

The term “dialkylaminosulfonyl,” as used herein, refers to adialkylamino group, as defined herein, appended to the parent molecularmoiety through a sulfonyl group. Representative examples ofdialkylaminosulfonyl include, but are not limited to,diethylaminosulfonyl, dimethylaminosulfonyl, ethylmethylaminosulfonyl,and the like.

The term “ethylenedioxy,” as used herein, refers to a —O(CH₂)₂O— groupwherein the oxygen atoms of the ethylenedioxy group are attached to theparent molecular moiety through one carbon atom forming a 5 memberedring or the oxygen atoms of the ethylenedioxy group are attached to theparent molecular moiety through two adjacent carbon atoms forming a sixmembered ring.

The term “formyl,” as used herein, refers to a —C(O)H group.

The term “formylalkyl,” as used herein, refers to a formyl group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of formylalkylinclude, but are not limited to, formylmethyl, 2-formylethyl, and thelike.

The term “halo” or “halogen,” as used herein, refers to —Cl, —Br, —I or—F.

The term “haloalkenyl,” as used herein, refers to at least one halogen,as defined herein, appended to the parent molecular moiety through analkenyl group, as defined herein. Representative examples of haloalkenylinclude, but are not limited to, 2,3,3-trifluoropropen-3-yl,2,2-difluoroethenyl, and the like.

The term “haloalkenyloxy,” as used herein, refers to a haloalkenylgroup, as defined herein, appended to the parent molecular moietythrough an oxy group, as defined herein. Representative examples ofhaloalkenyloxy include, but are not limited to,2,3,3-trifluoropropen-3-yloxy, 2,2-difluoroethenyloxy, and the like.

The term “haloalkoxy,” as used herein, refers to at least one halogen,as defined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, chloromethoxy, 2-fluoroethoxy,trifluoromethoxy, pentafluoroethoxy, and the like.

The term “haloalkoxyhydroxyalkyl,” as used herein, refers to ahaloalkoxy group, as defined herein, appended to the parent molecularmoiety through a hydroxyalkyl group, as defined herein. Representativeexamples of haloalkoxyhydroxyalkyl include, but are not limited to,4-(trifluoromethoxy)-1-hydroxybutyl, 4-(difluoromethoxy)-1-hydroxybutyl,and the like.

The term “haloalkyl,” as used herein, refers to at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.

The term “haloalkynyl,” as used herein, refers to at least one halogen,as defined herein, appended to the parent molecular moiety through analkynyl group, as defined herein. Representative examples of haloalkynylinclude, but are not limited to, 4,4,4-trifluorobutyn-2-yl,3,3-difluoropropy-1-yl, and the like.

The term “heterocycle” or “heterocyclic,” as used herein, refers to amonocyclic, bicyclic, or tricyclic ring system. Monocyclic ring systemsare exemplified by any 3- or 4-membered ring containing a heteroatomindependently selected from oxygen, nitrogen and sulfur; or a 5-, 6- or7-membered ring containing one, two or three heteroatoms wherein theheteroatoms are independently selected from nitrogen, oxygen and sulfur.The 5-membered ring has from 0-2 double bonds and the 6- and 7-memberedring have from 0-3 double bonds. Representative examples of monocyclicring systems include, but are not limited to, azetidinyl, azepinyl,aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, dithianyl, furyl,imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl,isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl,oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl,pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl, thiadiazolidinyl,thiazolyl, thiazolinyl, thiazolidinyl, thiophenyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl, thiopyranyl, triazinyl, triazolyl,trithianyl, and the like. Bicyclic ring systems are exemplified by anyof the above monocyclic ring systems fused to an aryl group as definedherein, a cycloalkyl group as defined herein, or another monocyclic ringsystem. Representative examples of bicyclic ring systems include but arenot limited to, for example, benzimidazolyl, benzothiazolyl,benzothiophenyl, benzoxazolyl, benzofuranyl, benzopyranyl,benzothiopyranyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl,indazolyl, indolyl, indolinyl, indolizinyl, naphthyridinyl,isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoindolinyl,isoquinolyl, phthalazinyl, pyranopyridyl, quinolyl, quinolizinyl,quinoxalinyl, quinazolinyl, tetrahydroisoquinolyl, tetrahydroquinolyl,thiopyranopyridyl, and the like. Tricyclic rings systems are exemplifiedby any of the above bicyclic ring systems fused to an aryl group asdefined herein, a cycloalkyl group as defined herein, or a monocyclicring system. Representative examples of tricyclic ring systems include,but are not limited to, acridinyl, carbazolyl, carbolinyl,dibenzofuranyl, dibenzothiophenyl, naphthofuranyl, naphthothiophenyl,oxanthrenyl, phenazinyl, phenoxathiinyl, phenoxazinyl, phenothiazinyl,thianthrenyl, thioxanthenyl, xanthenyl, and the like.

The heterocyclic groups of this invention can be substituted with 1, 2,or 3 substituents independently selected from alkenyl, alkenyloxy,alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkenyl,alkoxycarbonylalkyl, alkoxycarbonylalkylthio, alkyl, alkylamino,alkylaminosulfonyl, alkylcarbonyl, alkylcarbonylalkyl,alkylcarbonylamino, alkylcarbonyloxy, alkylimino, alkylsulfinyl,alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl,alkylsulfonylamino, alkylthio, alkylthioalkyl, alkylthioalkylcarbonyl,alkynyl, amino, aminocarbonyl, aminocarbonylalkoxy, aminosulfonyl, aryl,arylalkoxy, arylalkyl, aryloxy, arylcarbonyl, carboxy, carboxyalkenyl,carboxyalkoxy, carboxyalkyl, cyano, cyanoalkoxy, cyanoalkyl, cycloalkyl,dialkylamino, dialkylaminosulfonyl, ethylenedioxy, formyl, formylalkyl,halogen, haloalkoxy, haloalkyl, heterocyclic, heterocyclic alkoxy,heterocyclic alkyl, heterocyclic carbonyl, hydroxy, hydroxyalkoxy,hydroxyalkyl, methylenedioxy, mercapto, nitro, and sulfo.

The term “heterocyclic alkoxy,” as used herein, refers to a heterocyclicgroup, as defined herein, appended to the parent molecular moietythrough an alkoxy group, as defined herein. Representative examples ofheterocyclic alkoxy include, but are not limited to, 2-pyrid-3-ylethoxy,3-quinolin-3-ylpropoxy, 5-pyrid-4-ylpentyloxy, and the like.

The term “heterocyclic alkyl,” as used herein, refers to a heterocyclic,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of heterocyclicalkyl include, but are not limited to, pyrid-3-ylmethyl,2-pyrimidin-2-ylpropyl, and the like.

The term “heterocyclic alkylthio,” as used herein, refers to aheterocyclic alkyl group, as defined herein, appended to the parentmolecular moiety through a thio moiety, as defined herein.Representative examples of heterocyclic alkylthio include, but are notlimited to, 2-pyrid-3-ylethysulfanyl, 3-quinolin-3-ylpropysulfanyl,5-pyrid-4-ylpentylsulfanyl, and the like.

The term “heterocyclic carbonyl,” as used herein, refers to aheterocyclic, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples ofheterocyclic carbonyl include, but are not limited to,pyrid-3-ylcarbonyl, quinolin-3-ylcarbonyl, sulfanylphen-2-ylcarbonyl,and the like.

The term “heterocyclic oxy,” as used herein, refers to a heterocyclicgroup, as defined herein, appended to the parent molecular moietythrough an oxy moiety, as defined herein. Representative examples ofheterocyclic oxy include, but are not limited to, pyrid-3-yloxy,quinolin-3-yloxy, and the like.

The term “heterocyclic oxyalkyl,” as used herein, refers to aheterocyclic oxy group, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.Representative examples of heterocyclic oxyalkyl include, but are notlimited to, pyrid-3-yloxymethyl, 2-quinolin-3-yloxyethyl, and the like.

The term “heterocyclic thio,” as used herein, refers to a heterocyclicgroup, as defined herein, appended to the parent molecular moietythrough a thio moiety, as defined herein. Representative examples ofheterocyclic thio include, but are not limited to, pyrid-3-ylsulfanyl,quinolin-3-ylsulfanyl, and the like.

The term “heterocyclic thioalkyl,” as used herein, refers to aheterocyclic thio group, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.Representative examples of heterocyclic thioalkyl include, but are notlimited to, pyrid-3-ylsulfanylmethyl, 2-quinolin-3-ylsulfanylethyl, andthe like.

The term “hydroxy,” as used herein, refers to an —OH group.

The term “hydroxyalkoxy,” as used herein refers to 1 or 2 hydroxygroups, as defined herein, appended to the parent molecular moietythrough an alkoxy group, as defined herein. Representative examples ofhydroxyalkoxy include, but are not limited to, hydroxymethoxy,2-hydroxyethoxy, 2-hydroxy-2-methylethoxy, 3-hydroxy-1-propoxy,4-hydroxy-1-butoxy, 3-hydroxy-3-methyl-1-butoxy,2,3-dihydroxy-1-propoxy, and the like.

The term “hydroxyalkyl,” as used herein, refers to 1 or 2 hydroxygroups, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl,2,3-dihydroxypropyl, and the like.

The term “hydroxyimino,” refers to a HON=group.

The term “hydroxyiminoalkoxy,” as used herein, refers to a hydroxyiminogroup, as defined herein; appended to the parent molecular moietythrough an alkoxy group, as defined herein. Representative examples ofhydroxyiminoalkoxy include, but are not limited to, hydroxyiminomethoxy,2-hydroxyminoethoxy, 2-hydroxyiminopropoxy, and the like.

The term “hydroxyiminoalkyl,” as used herein, refers to a hydroxyiminogroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofhydroxyiminoalkyl include, but are not limited to, hydroxyiminomethyl,2-hydroxyiminoethyl, 2-hydroxyiminopropyl, and the like.

The term “imino,” as used herein, refers to a HN=group.

The term “iminoalkoxy,” as used herein, refers to an imino group, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of aminoalkoxyinclude, but are not limited to, 2-iminoethoxy, 2-imino-1-propoxy,3-imino-1-butoxy, and the like.

The term “iminoalkyl,” as used herein, refers to an imino group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of iminoalkyl include,but are not limited to, 2-iminoethyl, 2-imino-1-propyl, 3-imino-1-butyl,and the like.

The term “mercapto,” as used herein, refers to a —SH group.

The term “mercaptoalkoxy,” as used herein, refers to a mercapto group,as defined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples ofmercaptoalkoxy include, but are not limited to, 2-mercaptoethoxy,3-mercaptopropoxy, and the like.

The term “mercaptoalkyl,” as used herein, refers to a mercapto group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of mercaptoalkylinclude, but are not limited to, 2-mercaptoethyl, 3-mercaptopropyl, andthe like.

The term “methylenedioxy,” as used herein, refers to a —OCH₂O— groupwherein the oxygen atoms of the methylenedioxy are attached to theparent molecular moiety through two adjacent carbon atoms.

The term “nitro,” as used herein, refers to a —NO₂ group.

The term “oxo,” as used herein, refers to a ═O moiety.

The term “oxy,” as used herein, refers to a —O— moiety.

The term “phosphonato,” as used herein, refers to a (R₈₄O)₂P(O)O— groupwherein R₈₄ is selected from hydrogen and alkyl, as defined herein.

The term “phosphonatoalkoxy,” refers to a phosphonato group, as definedherein, appended to the parent molecular moiety through an alkoxy group,as defined herein. Representative example of phosphonatoalkoxy include,but are not limited to, 3-hydroxypropyl dihydrogen phosphate,3-hydroxy-1,1-dimethylpropyl dihydrogen phosphate, and the like.

The term “sulfinyl,” as used herein, refers to a —S(O)— group.

The term “sulfo,” as used herein, refers to a —SO₃H group.

The term “sulfonyl,” as used herein, refers to a —S(O)₂— group.

The term “thio,” as used herein, refers to a —S— moiety.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfaie, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as loweralkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of the compounds of formula I, or separately byreacting a carboxylic acid function with a suitable base such as thehydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia, or an organic primary, secondary ortertiary amine. Such pharmaceutically acceptable salts include, but arenot limited to, cations based on the alkali and alkaline earth metals,such as sodium, lithium, potassium, calcium, magnesium, aluminum saltsand the like, as well as nontoxic ammonium, quaternary ammonium, andamine cations, including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, ethylamine, and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine and the like.

The term “pharmaceutically acceptable ester” as used herein refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters includes formates, acetates, propionates,butyates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrug” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention. The term “prodrug” refers to compounds that are rapidlytransformed in vivo to provide the parent compound having the aboveformula, for example by hydrolysis in blood. A thorough discussion isprovided in T. Higuchi and V. Stella, Pro-drugs as Novel DeliverySystems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche,ed., Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

As used throughout this specification and the appended claims, the termmetabolically cleavable group denotes a moiety which is readily cleavedin vivo from the compound bearing it, wherein said compound, aftercleavage remains or becomes pharmacologically active. Metabolicallycleavable groups form a class of groups reactive with the carboxyl groupof the compounds of this invention are well known to practitioners ofthe art. They include, but are not limited to groups such as, forexample, alkylcarbonyl, such as acetyl, propionyl, butyryl, and thelike; unsubstituted and substituted arylcarbonyl, such as benzoyl andsubstituted benzoyl; alkoxycarbonyl, such as ethoxycarbonyl;trialkylsilyl, such as trimethyl- and triethysilyl; monoesters formedwith dicarboxylic acids, such as succinyl, and the like. Because of theease with which the metabolically cleavable groups of the compounds ofthis invention are cleaved in vivo, the compounds bearing such groupsact as pro-drugs of other prostaglandin biosynthesis inhibitors. Thecompounds bearing the metabolically cleavable groups have the advantagethat they may exhibit improved bioavailability as a result of enhancedsolubility and/or rate of absorption conferred upon the parent compoundby virtue of the presence of the metabolically cleavable group.

Asymmetric centers may exist in the compounds of the present invention.The present invention contemplates the various stereoisomers andmixtures thereof. Individual stereoisomers of compounds of the presentinvention are made by synthesis from starting materials containing thechiral centers or by preparation of mixtures of enantiomeric productsfollowed by separation as, for example, by conversion to a mixture ofdiastereomers followed by separation by recrystallization orchromatographic techniques, or by direct separation of the opticalenantiomers on chiral chromatographic columns. Starting compounds ofparticular stereochemistry are either commercially available or are madeby the methods detailed below and resolved by techniques well known inthe organic chemical arts.

The present invention discloses pyridazinone compounds which arecyclooxygenase (COX) inhibitors and are selective inhibitors ofcyclooxygenase-2 (COX-2). COX-2 is the inducible isoform associated withinflammation, as opposed to the constitutive isoform, cyclooxygenase-1(COX-1) which is an important “housekeeping” enzyme in many tissues,including the gastrointestinal (GI) tract and the kidneys.

Preferred compounds of the present invention include, but are notlimited to,

-   2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(4-fluorophenyl)-5-methoxy-3(2H)-pyridazinone;-   2-Benzyl-4-(4-fluorophenyl)-5-hydroxy-3(2H)-pyridazinone;-   2-Benzyl-4-(4-fluorophenyl)-5-(trifluoromethylsulfonyloxy)-3(2H)-pyridazinone;-   2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Phenyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(Phenylpropargyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,4-Difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(Methyl-2-propenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Methyl-2-butenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2-Trifluoromethylbenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(Cyclopropylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2-Pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(6-Fluoroquinolin-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(Quinolin-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinethione-   2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,3-Dichloro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Phenyl-2-propenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Carboxyphenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(5-Methylthiazol-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(5-Chlorothiazol-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,3,3,4,4,4-Hexafluorobuten-1-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,4-Difluorophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(5-Chlorothien-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(5-Methylthien-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Diethylaminophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,3,4,5,6-Pentafluorobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(Phenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Chlorophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(Propargyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Cyanophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(α-Methyl-4-fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Phenethyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(3-chloro-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-chloro-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Trifluoromethoxyphenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Trifluoromethylphenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-[2-(Benzo[b]thien-3-yl)-2-oxoethyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,3-Dimethyl-2-oxobutyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Thienylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2-Benzo[b]thienylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2,4-Bis(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-6-methyl-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-6-methyl-3(2H)-pyridazinone;-   2-Benzyl-4-(3,4-dichlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-n-propylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-chloro-3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-chlorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2M-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-fluorophenoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2,4-Bis-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)₂₄-(4-chloro-3-fluorophenyl)-5-[4-(aminosulfonyl)-phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-chlorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-chloro-3-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3,4-dichlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(2-propylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-cyclohexyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-cyclopentyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2-propylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(4-morpholino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,3,3-Trifluoro-2-propen-1-yl)]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2,4-Bis(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-cyclopropylmethoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-propen-1-oxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-fluoro-α-methylbenzyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-[4-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2,5-Bis[4-(methylsulfonyl)phenyl]-4-(4-fluorophenyl)-3(2H)-pyridazinone;-   2-(3-Methyl-2-thienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2-Trifluoromethyl-4-nitrophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-[3-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-[3-(Methylsulfonyl)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(5-Chloro-2-thienyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-[2-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(5-Nitro-2-thienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Benzothienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Bromophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,5-Difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Nitrobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Acetoxybenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Hydroxybenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Nitrobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4,4-Trifluoro-3-butenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2-Hexynyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,3-Dichloro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Cyclohexyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Cyclopentyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Cyclobutyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Methyl-2-butenyl)-4-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,4-Difluorobenzyl)-4-(4-fluorophenyl)-5-[4-aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(Pentafluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Cyclohexenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,3-Dihydro-1H-inden-2-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,3-Dihydro-1H-inden-1-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Tetrahydro-2H-pyran-4-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2-Methylcyclopentyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2-Adamantyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Methylcyclopentyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(1-Methylcyclopentyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-fluoro-3-vinylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(6-methyl-3-heptenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3-cyclopropylidenepropyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(5-methyl-3-hexenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(5-methylhexyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-1-methyl-2E-propenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,3,3-Trifluoro-2-propen-1-yl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(1,1,2-Trifluoro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,3-Difluoro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(α-Methyl-3-fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(1-Cyclohexenylmethyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(α-Methyl-2,3,4-trifluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(α-Methyl-3,5-difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(α-Methyl-3,4-difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3    (2H)-pyridazin one;-   2-(3-Fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,4,6-Trifluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,4,5-Trifluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,3,4-Trifluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3    (2H)-pyridazinone;-   2-(4,4,4-Trifluoro-3-methyl-2E-butenyl)-4-(4-fluorophenyl)-5-[4-(amino    sulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Biphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Bromophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazin    one;-   2-(4-Nitrophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3    (2H)-pyridazinone;-   2-(4-Phenoxyphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-t-Butylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Chlorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3    (211)-pyridazinone;-   2-(3-Methylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Vinylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(211)-pyridazinone;-   2-(2-Formylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2-Nitrophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Bromophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Cyanophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(5-Methyl-2-thienyl))-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Biphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,5-Dimethylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2-Thienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Trifluoromethylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-[4-(1-Pyrroyl)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(5-Chloro-2-thienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2(4-Methylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(2-ethyl-1-hexyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Thienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,5-Difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;    pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Furyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Fluoro-4-methoxyphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2-Fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-[4-(Aminosulfonyl)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,5-Dichlorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluoro-3-methylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Chloro-3-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Chloro-2-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(1-Adamantyloxycarbonyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(4-fluorophenoxymethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(3-fluorophenoxymethyl)-5-[4-methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-phenoxymethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(t-butylthiomethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(2-methylpropylthiomethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(2-propoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Fluorophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Bromophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,5-Difluorophenyl)₇₄-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-   3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(4-fluorophenoxymethyl)-5-[4(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(benzoyloxymethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3,5-dichlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-ethoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-trifluoromethylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-nitrophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-vinylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-[3-(trifluoromethyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3,5-difluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2-propenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2-buten-2-yl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(1-cyclohexenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(phenylethynyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-vinyl-3(2H)-pyridazinone,-   2-(3,4-Difluorophenyl)-4-(2-thienyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(1-propynyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-t-butyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(3,5-difluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2(4-Fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(aminosulfonyl)phenyl]-3(2)    pyridazinone;-   2-(3,4-Difluorophenyl)-4-(phenylethynyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3,4-difluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-[4-Fluoro-3-(methylthio)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-methoxyphenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2-fluoro-5-trifluoromethylphenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-cyanophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-pyridyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-n-propylphenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-[4-(methylsulfonyl)phenoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-phenylphenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-[2-(methylthio)ethoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(phenylmethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2-furylmethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-[2-(3,4-dimethoxyphenyl)ethoxy)]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-[2-(4-morpholino)ethoxy)]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-[2-(1-piperidinyl)ethoxy)]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-[4-(carboxamido)phenoxy)]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(1-indanyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-[4-(acetamido)phenoxy)]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(1-methylcyclopropylmethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3,3-dimethylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-chlorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-bromophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(cyclopentylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(1H-1,2,4-triazole-3-ylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-phenylmethylthio-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-fluorophenylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(cyclohexylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-chloro-4-fluorophenylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2,2,2-trifluoroethylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(tert-butylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-acetamidophenylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2-propylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2-methylpropylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-amino-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-methoxypropylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(cyclopentylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(cyclobutylamino)-5-[4-(methylsulfonyl)phenyl]—3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3,4-dimethoxyphenethylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(cyclohexylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-[2-(1-piperidinyl)ethylamino]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2-tetrahydrofurfurylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(cyclopropylmethylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2,3-dihydro-1H-inden-1-ylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(1-piperidinyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-hydroxypropylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-[3-(1H-imidazol-1-yl)propylamino]-5-[4-(methylsulfonylphenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2R-hydroxypropylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2-cyanoethylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-cyanoanilino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-[3-methoxy-5-(trifluoromethyl)anilino]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-anilino-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2,5-dimethoxyphenylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-fluoroanilino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2,4-difluoroanilino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2,3,5-trifluoroanilino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(4-fluoroanilino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(3-thienyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(2-benzofuranyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(5-chloro-2-thienyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(3-nitrophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(4-vinylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(4-trifluoromethylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(2-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(3,4-dimethylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(2-methoxypyrid-3-yl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(3-ethoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-(2H)-pyridazinone;-   2-(tert-Butyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(t-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(cyclohexyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(3-octyn-1-yloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-[2-(dimethylamino)ethoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-[2-methyl-1-(1-methylethyl)propoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(phenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-[3-(dimethylamino)phenoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(4-methoxyphenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-fluorophenoxy)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-[2-(isopropoxy)ethoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3-methylpentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-methyl-3-penten-1-yloxy)-5-[4-(methylsulfonyl)phenyl]-5-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-[3-(methoxy)butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(N-methylbenzylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(1-piperidinyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(1-pyrrolidinyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(4-methylphenylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(2-pyridylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(phenylmethylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(2-furylmethylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-]2-(methylpropyl)thio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(cyclopentyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(2-methylpropyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(cyclopentylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(2-cyclopentylethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(phenethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(benzyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(Tetrahydro-2H-pyrano-2-2-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-(4-Fluorophenyl)phenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(4-fluorobenzyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(4-fluorophenoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(3-methylbutyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(phenethyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(3-methylbutoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(3-methylbutyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(2-methylpropoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(3-methylbutoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(t-Butyl)-4-(3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(2-methylpropoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3-methylbutyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(2,2-dimethylpropoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-fluorophenoxy)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,3-Difluoro-2-propenyl)]-4-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-[2-(2-propoxy)ethoxy]-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(3-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(4-methylpentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(4-methylpentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-cyclopropylmethoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(2-cyclopropyl-1-ethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-cyclopropanemethoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(2-cyclopropane-1-ethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(4-methylpentyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(4-methylpentyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(3-methyl-2-butenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(3-methyl-2-butenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(3-methyl-3-butenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(3-methyl-3-butenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(1,5-hexadienyl-3-oxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(5-methyl-2-hexyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(2-ethyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(2-thioisopropyl-1-ethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(3-methylthio-1-hexyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(2-methyl-4-pentenyl-1-oxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3-trifluoromethyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-ethoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-methyl-1-pentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-methyl-2-pentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(2-cyclopentyl-1-ethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(2-cyclopent-2-enyl-1-ethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2-Hydroxy-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2-Methoxy-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2-Methoxyimino-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-methylpentyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-methylbutoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2-methylpropoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,3,3-Trifluoropropenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,3,4,5,6-Pentafluorobenzyl)-4-(4-fluorophenyl)-5-[4-(dimethylamino)methylaminosulfonylphenyl]-3(2H)-pyridazinone;-   2-(2,4-Difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(dimethylamino)methylaminosulfonylphenyl]-3(2H)-pyridazinone;-   (4-Fluorophenyl)-5-[4-(methylselenonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(2-oxo-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-[2-(methoxyimino)-1-propoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3-oxo-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(3-oxo-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(4-hydroxy-2-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   S    2-(3-Chloro-4-fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(4-Fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(4-Fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-Fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(aminosulfonyl)-phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(amino-sulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chlorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   N-[[4-[2-(3,4-Difluorophenyl)-4-(2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide;-   N-[[4-[2-(3,4-Difluorophenyl)-4-(2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]-sulfonyl]acetamide,    sodium salt;-   N-[[4-[2-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide;-   N—[[4-[2-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide,    sodium salt;-   N—[[4-[2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide;-   N-[[4-[2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide,    sodium salt;-   N—[[4-[2-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide;-   N—[[4-[2-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide,    sodium salt;-   N—[[4-[2-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide;-   N—[[4-[2-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide,    sodium salt;-   N—[[4-[2-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide;-   N—[[4-[2-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide,    sodium salt;-   N—[[4-[2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide;-   N—[[4-[2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide,    sodium salt;-   2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Dichlorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-[(3-Trifluoromethyl)phenyl]-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Dichlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(24)-pyridazinone;-   (R,S)-2-(4-Fluorophenyl)-4-(3-hydroxy-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-Chloro-4-fluorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Dichlorophenyl)-4-(2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Dichlorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-hydroxy-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-[3-(Trifluoromethyl)phenyl]-4-(2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-[3-(Trifluoromethyl)phenyl]-4-(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-[3-(Trifluoromethyl)phenyl]-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-1    butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(3,4-Difluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(4-chlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(3-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(3-chlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(3-bromophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;    —-   (S)-2-(3-trifluoromethylphenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(3-chloro-4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(3-fluoro-4-chlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(3,4-dichlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(3-trifluoromethyl-4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (S)-2-(3-bromo-4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(3,4-Difluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(4-chlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(3-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(3-chlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(3-bromophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(3-trifluoromethylphenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(3-chloro-4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(3-fluoro-4-chlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(3,4-dichlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(3-trifluoromethyl-4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   (R)-2-(3-bromo-4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-fluorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-chlorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-fluorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-chlorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-bromophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-trifluoromethylphenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-chloro-4-fluorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-fluoro-4-chlorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-dichlorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-trifluoromethyl-4-fluorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-bromo-4-fluorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-fluorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-chlorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-fluorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-chlorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-bromophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-trifluoromethylphenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-chloro-4-fluorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-fluoro-4-chlorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-dichlorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-fluoro-3-trifluoromethylphenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-bromo-4-fluorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-fluorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-chlorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-fluorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-chlorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-bromophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-trifluoromethylphenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-chloro-4-fluorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-fluoro-4-chlorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-fluoro-3-trifluoromethylphenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-bromo-4-fluorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-fluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-chlorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-fluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-chlorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-bromophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-trifluoromethylphenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-chloro-4-fluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-fluoro-4-chlorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-dichlorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-fluoro-3-trifluoromethylphenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-bromo-4-fluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-Difluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-fluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1    butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(4-chlorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-fluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-chlorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-bromophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-trifluoromethylphenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-chloro-4-fluorophenyl)-4-[3-{[(2R,3R)-3-caboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-fluoro-4-chlorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3,4-dichlorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-trifluoromethyl-4-fluorophenyl)-4-[3-{[2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(3-bromo-4-fluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   3-({2-(3,4-difluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl    dihydrogen phosphate;-   3-({2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl    dihydrogen phosphate;-   3-({2-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl    dihydrogen phosphate;-   3-({2-(3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl    dihydrogen phosphate;-   3-({2-(3-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl    dihydrogen phosphate;-   3-({2-(3-bromophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl    dihydrogen phosphate;-   3-({2-(3-trifluoromethylphenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl    dihydrogen phosphate;-   3-({2-(3-chloro-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl    dihydrogen phosphate;-   3-({2-(3-fluoro-4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl    dihydrogen phosphate;-   3-({2-(3,4-dichlorophenyl)-5-[4(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl    dihydrogen phosphate;-   3-({2-(3-trifluoromethyl-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl    dihydrogen phosphate;-   3-({3-bromo-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl    dihydrogen phosphate;-   2-(tert-Butyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(tert-Butyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;-   2-(tert-butyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;    and-   3-({2-(tert-butyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl    dihydrogen phosphate; or pharmaceutically acceptable salts or    prodrugs thereof.

Preparation of Compounds of the Invention Abbreviations

As used throughout this specification and the appended claims, thefollowing abbreviations have been used:

ACD for acid citrate dextrose, CAP for carrageenan induced air pouchprostaglandin; CIP for rat carrageenan pleural inflammation model, COX-2for cyclooxygenase-2, CPE for carrageenan induced paw edema in rats,DBAD for di-t-butylazodicarboxylate, DEAD for diethyl azodicarboxylate,T)LAD for disopropylazodicarboxylate, DMAP for4-(dimethylamino)pyridine, DME for 1,2-dimethoxyethane, DMF forN,N-dimethylformamide, DMSO for dimethyl sulfoxide, DMSO for dimethylsulfoxide, EDTA for ethylenediaminetetraacetic acid, EIA for enzymeimmunoassay, FAB for fast atom bombardment, GI for gastrointestinal,HMDS, lithium or Li HMDS for lithium 1,1,1,3,3,3-hexamethyldisilazide,HWPX for Human Whole Platelet Cyclooxygenase-1, MCPBA formeta-chloroperoxybenzoic acid, NSAIDs for non-steroidalanti-inflammatory drugs, PEG 400 for polyethyleneglycol, PGE₂ forprostaglandin E₂, PGHS for prostaglandin endoperoxide H synthase, RHUCX1for recombinant human cyclooxygenase-1, RHUCX2 for recombinant humancyclooxygenase-2, r-hu Cox1 for recombinant human Cox-1, TEA fortriethylamine, TFA for trifluoroacetic acid, and THF for tetrahydrofuranand WISH for human amnionic whole cell cyclooxygenase-2. The followingexamples illustrate the process of the invention, without limitation.

The compounds of the invention may be prepared by a variety of syntheticroutes. Representative procedures are outlined in Schemes 1-10, below.

A general route to the compounds of the invention having Formula III,where the aryl group at the 5-position on the pyridazinone ring issubstituted with a sulfonyl group is described in Scheme 1.Dichloro-3(2H)-pyridazinone can be treated with benzyl chloride andpotassium carbonate in methanol to provide2-benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone.2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone can be treated with aboronic acid such as 4-fluorobenzeneboronic acid (shown) and a palladiumcatalyst and the methoxy group can be hydrolyzed with 48% hydrobromicacid to provide the 5-hydroxypyridazinone compound. The5-hydroxypyridazinone product can be treated with triflic anhydridefollowed by substitution on the pyridazinone ring using4-methylthiobenzeneboronic acid to provide the methyl thioethercompound. The methyl thioether compound which can be treated withperacetic acid in acetic acid and methylene chloride to provide themethyl sulfone. The benzyl group can be removed using aluminum bromideor another suitable Lewis acid. The R group can be added using anappropriate alkylating agent and base.

An alternative route to the compounds of the present invention havingFormula III is described in Scheme 2. 4-Bromothioanisole or anothersuitable thioether can be treated with a trialkoxyborate, such astrimethoxyborate or triisopropylborate to provide4-(methylthio)benzeneboronic acid. The boronic acid can be treated with2-benzyl-4,5-dibromo-3(2H)-pyridazinone usingtetrakis(triphenylphosphine)palladium (0) in dimethoxyethane and thencoupled with a second boronic acid such as 4-fluorobenzeneboronic acid(shown) in the presence of a palladium catalyst to provide thethioether. The methyl thioether compound can be treated withmeta-chloroperoxybenzoic acid (MCPBA) in methylene chloride to providethe methyl sulfone.

An alternative route to the compounds of the present invention havingFormula III is described in Scheme 3.(4-Thiomethylphenyl)dimethylthioketene acetal, mono-S-oxide can beprepared by reaction of 4-thiomethylbenzaldehyde (Y is CH₃S) withmethyl(methylsulfinylmethyl)sulfide and sodium hydroxide. The thioketeneacetal and methyl 4-fluorophenylacetate or suitable ester (X isfluorine) can be treated with a strong base such as sodiumhexamethyldisilazide in THF to provide the butyrate ester. Thedithioacetal ketene can be directly cyclized to the N-unsubstitutedpyridazinone using hydrazine and a salt. The pyridazinone can be then bealkylated using an appropriate alkylating agent and a base.

In an alternate route, shown in Scheme 4, the thioacetal ketene (X═F andY═CH₃S) can be treated with perchloric acid to provide an ester-aldehydeas a mixture of diastereomers. The oxidation products can be treatedwith hydrazine and then oxidized with peroxyacetic acid to provide thesulfonyl dihydropyridazinone (Y═CH₃SO₂). The dihydropyridazinone can bedehydrogenated to form the pyridazinone by treatment with reagents suchas bromine in acetic acid. The R group may be added via substitutionusing an appropriate alkylating agent and base.

The preparation of the 5-hydroxy-2(5H)-furanones can be accomplished bythe application of methodologies published in a variety of sources,including: J. Med. Chem., 1987, 30, 239-249 and WO 96/36623, herebycompletely incorporated by reference. These 5-hydroxy-2(5H)-furanonescan be converted to 6-substituted-4,5-diaryl-3(2H)pyridazinones asdescribed in Scheme 5.

A general route to the compounds of the invention having Formula III,where the aryl group at the 5-position on the pyridazinone ring issubstituted with a para-sulfonyl group is described in Scheme 6. Amucohalo acid, such as mucobromic or mucochloric acid, can be treatedwith an hydrazine having the desired R group to provide thedihalopyridazinone compound, 6A. The dihalo-compound can be treated withan alcohol in the presence of a base, such as sodium or potassiumhydride, to provide an alkoxide 6B where R⁹⁷ is selected from alkyl,aryl, arylalkyl, heterocyclic, and heterocyclic alkyl. (If the alkoxygroup is to be removed at a later time then methanol is the preferredalcohol.) The alkoxy-halide can be treated with methylthiophenylboronicacid to provide the alkoxy-pyridazinone 6C. The alkoxy group can beconverted to a hydrocarbyl group by treatment with a Grignard reagent toprovide thioether 6D where R⁹⁶ is alkyl. The thioether 6D can beoxidized with an oxidizing agent, such as peracetic acid,meta-chloroperoxybenzoic acid and the like, to form the sulfinylcompound 6G, or the methylsulfone compound 6E. The methylsulfinylcompound, 6G, can be treated with trifluoroacetic anhydride andNaOH/MeOH followed by addition of chlorine gas and then ammoniahydroxide to provide the aminosulfonyl compound, 6H. Alternatively, themethylsulfonyl compound, 6E, can be treated with a diazodicarboxylate,such as DBAD, DIAD, DEAD and the like, and a disilazane anion, such aslithium HMDS and the like, followed by treatment with sodium acetate andhydroxylamine-O-sulphonic acid in water to provide the aminosulfonylcompound, 6H.

Methylsulfonyl alkoxy pyridazinones and aminosulfonyl alkoxypyridazinones can be prepared as described in Scheme 7.Alkoxy-pyridazinone, 6C, from Scheme 6, can be oxidized using peraceticacid to provide methyl sulfone, 7A. Methyl sulfone alkoxy pyridazinone,7A, can be treated as described in Scheme 6 to provide aminosulfonylalkoxy pyridazinone, 7B. Alternatively, alkoxy-pyridazinone 6C, fromScheme 6, can be oxidized with one equivalent ofmeta-chloroperoxybenzoic acid or one equivalent ofhydroxy(tosyloxy)iodobenzene to provide the methylsulfinyl alkoxypyridazinone, 7C. Methylsulfinyl alkoxy pyridazinone, 7C, can be treatedas described in Scheme 6 to provide aminosulfonyl alkoxy pyridazinone,7B.

Pyridazinones of general formula 8D and 8E, wherein R⁸⁰ is hydroxyalkyl,and A and B are selected from alkenyl, alkyl, haloalkyl, and halogen,can be prepared as described in Scheme 8. Pyridazinones of generalformula 8A can be treated with diols and a base such as sodium hydrideor potassium hydride in THF to selectively provide 4-substitutedpyridazinones of general formula 8B. 4-Substituted pyridazinones ofgeneral formula 8B can be treated with 4-(methylthio)phenylboronic acid,a base such as potassium carbonate, and a palladium catalyst such asdichlorobis(triphenylphosphine)palladium(1H) in ethanol to providemethylthio compounds of general formula 8C. Methylthio compounds ofgeneral formula 8C can be oxidized with meta-chloroperoxybenzoic acid orperacetic acid to provide methylsulfones of general formula 8D.Methylsulfones of general formula 8D can be processed as described inScheme 6 to provide aminosulfonyl compounds of general formula 8E.Alternatively, methylthio compounds of general formula 8C can beoxidized to the sulfoxide and then processed as described in Scheme 6 toprovide aminosulfonyl compounds of general formula 8E.

Preparation of Compounds of the Invention Having Formula III, where theGroup at the 4-position on the pyridazinone ring is a substituted alkylor alkenyl group is described in Scheme 9. Pyridazinone 9A can betreated with a halogenating reagent, such as NBS and peroxide, toprovide bromo compound 9B. The bromo compound can be reacted with analcohol and a weak base, such as sodium or potassium carbonate, toprovide 4-alkyl-ether, 9C where R⁹⁵ is alkyl. Alternatively, bromocompound 9B can be treated with a thio compound in the presence of abase, such as silver carbonate, to provide 4-alkyl-thioether, 9D whereR⁹⁴ is alkyl. Alternatively, bromo compound 9B can be treated with anamine and a weak base, such as sodium or potassium carbonate to provide4-alkylaminoalkyl compound 9E where R⁹³ is alkyl.

A general route to the compounds of the present invention having FormulaIII, where the group at the 4-position on the pyridazinone ring can bereadily substituted is illustrated in Scheme 10. Alkoxide, 10A, whereR⁹⁷ is methyl, can be treated with a base, such as sodium or potassiumhydroxide, to provide 4-hydroxy-pyradizinone, 10B. The alcohol can betreated with p-toluenesulfonyl chloride to provide tosyloxy compound,10C. The tosyloxy compound can be readily substituted with a compoundR⁹²Z that can undergo a S_(N)AR reaction. Examples of these compoundsare alcohols, thiols, amines or hydrocarbyl anions.

Compounds of the present invention include, but are not intended to belimited to, the following Examples:

EXAMPLE 1 4-(Methylthio)benzeneboronic acid

A stirred solution of 4-bromothioanisole (5.0 g, 0.0246 mol) inanhydrous tetrahydrofuran (THF) was chilled to −78° C. under a nitrogenatmosphere. A 2.5 M solution of n-butyl lithium (12 mL, 0.030 mol) inhexanes was added dropwise to the chilled solution. When the additionwas complete, the reaction mixture was stirred at −78° C. for about 45minutes. Trimethylborate (8.5 mL, 0.0748) was introduced via syringe.The reaction mixture was then allowed to warm to room temperatureovernight. The room temperature solution was treated successively with10% aqueous sodium hydroxide solution (50 mL) and water (33.5 mL) andstirred at room temperature for 1 hour. The reaction mixture was loweredto about pH=4-5 using 10% aqueous citric acid and the THF was removedunder reduced pressure. The aqueous residue was saturated with sodiumchloride and extracted with ethyl acetate. The organic extract was driedover MgSO₄ and filtered. The filtrate was concentrated under reducedpressure to provide a white solid which was washed with hexanes toprovide the product as a white solid (yield: 1.5 g; 36%). mp 170° C. ¹HNMR (300 MHz, DMSO-d₆) δ 2.47 (s, 3H), 7.20 (d, J=8 Hz, 2H), 7.71 (d,J=8 Hz, 2H), 7.96 (br s, 2H).

EXAMPLE 2 2-Benzyl-4,5-dibromo-3(2H)-pyridazinone

Benzyl bromide (0.59 mL, 0.005 mol) was added to a stirred solution of4,5-dibromo-3(2H)-pyridazinone (1.27 g, 0.005 mol) and potassiumcarbonate (0.76 g, 0.0055 mol) in 20 mL of anhydrous dimethylformamide(DMF). The solution was stirred overnight at room temperature, andpartitioned between aqueous citric acid and ethyl acetate. The aqueouslayer was extracted twice with ethyl acetate. The combined organicextracts were washed with brine, dried over MgSO₄ and filtered. Thefiltrate was concentrated under reduced pressure to provide a beigesolid, which was purified by column chromatography (silica gel, 9:1hexanes/ethyl acetate). The product was obtained as a white solid(yield: 1.32 g, 76.7%). mp 95-96° C. ¹H NMR (300 MHz, CDCl₃) δ 5.31 (s,2H), 7.29-7.37 (m, 3H), 7.41-7.47 (m, 2H), 7.79 (s, 1H). MS (DCI/NH₃)m/z 345 (M+H)⁺. IR (KBr) 1645 cm⁻¹.

EXAMPLE 3 2-Benzyl-4-bromo-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

A solution of the boronic acid (0.318 g, 0.0 mol), from Example 1, thedibromopyridazinone (0.975 g, 0.0 mol), prepared according to the methodof Example 2, and tetrakis(triphenylphosphine)palladium (0) (0.16 g,0.0142 mol), in dimethoxyethane (30 mL) was prepared. A 2 M aqueoussolution of sodium carbonate (2.83 mL, 0.0 mol) was added to thedimethoxyethane solution and the mixture was heated at reflux. After 16hours, a chromatographic (TLC) check (9:1 hexanes/ethyl acetate)indicated that both starting materials were still present and a freshaliquot of palladium catalyst was added. The reaction mixture wasstirred at reflux for an additional 5 hours, allowed to cool to roomtemperature and stand over the weekend. The volatile materials wereremoved under reduced pressure and the residue was partitioned betweenwater and ethyl acetate. The aqueous layer was extracted with ethylacetate. The combined organic extracts were washed with brine, driedover MgSO₄, and filtered. The filtrate was concentrated under reducedpressure to provide an oil which was purified by column chromatography(silica gel, 95:5 hexanes/ethyl acetate). Fractions containing thedesired product were combined and concentrated under reduced pressure.This material was rechromatographed (95:5 hexanes/ethyl acetate) tofurnish 0.200 g of a beige solid. The solid was crystallized fromether/hexanes to provide white crystals (yield: 110 mg, 15%) mp 115-118°C. ¹H NMR (300 MHz, CDCl₃) δ 2.53 (s, 3H), 5.40 (s, 2H), 7.30-7.42 (m,7H), 7.49-7.54 (m, 2H), 7.65 (s, 1H). MS (DCI/NH₃) m/z 387 (M+H)⁺.

EXAMPLE 42-Benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

A solution of the product from Example 3, (0.100 g, 0.0 mol),4-fluorobenzeneboronic acid (0.072 g, 0.0 mol),tetrakis(triphenylphosphine)palladium (0) (0.015 g, 0.0 mol), and a 2 Maqueous solution of sodium carbonate (0.64 mL, 0.0 mol) in 30 mL ofdimethoxyethane (DME) was stirred at reflux for 16 hours. A freshaliquot of palladium catalyst was added with an additional equivalent ofthe boronic acid. The reaction was maintained at reflux for 24 hours.The volatile materials were removed under reduced pressure and theresidue was partitioned between water and ethyl acetate. The aqueouslayer was extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over MgSO₄, and filtered. The filtrate wasadsorbed onto silica gel. The silica gel/product was placed at the topof a column of silica gel and the product eluted with 93:7 hexanes/ethylacetate. Fractions containing product Were combined and concentratedunder reduced pressure. The residue was purified further by a secondcolumn chromatography (silica gel, 95:5 hexanes/ethyl acetate).Fractions containing product were concentrated under reduced pressure toprovide a viscous oil (yield: 0.028 g, 27%). ¹H NMR (300 MHz, CDCl₃) δ2.46 (s, 3H), 5.39 (s, 2H), 6.95 (t, J=9 Hz, 2H), 6.99 (d, J=9 Hz, 2H),7.11 (d, J=9 Hz, 2H), 7.16-7.23 (m, 2H), 7.30-7.40 (m, 3H), 7.52-7.57(m, 2H), 7.86 (s, 1H). MS (DCI/NH₃) m/z 403 (M+H)⁺.

EXAMPLE 52-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A solution of meta-chloroperoxybenzoic acid (MPCBA) (0.039 g, 0.00013mol) in dichloromethane (5 mL) was added dropwise to a stirred solutionof the sulfide (0.027 g, 0.0 mol), from Example 4, in chilled (0° C.)dichloromethane (10 mL). After 5 minutes, TLC (1:1 hexanes/ethylacetate) indicated that the starting sulfide had been consumed. Thereaction was quenched with aqueous sodium sulfite. The organic layer waswashed twice with aqueous sodium hydroxide and once with brine. Thedichloromethane solution was dried over MgSO₄, and filtered. Thefiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel, 7:3 hexanes/ethylacetate) to provide the desired sulfone product. Further elution with100% ethyl acetate removed the sulfoxide from the column. The sulfoxideproduct was re-subjected to the MCA oxidant (0.04 g, 1 hour, 0° C.) andworked-up as described above. The residue obtained was combined with thesulfone from the first column and the mixture was purified by columnchromatography (silica gel, 7:3 hexanes/ethyl acetate). Fractionscontaining product were combined and concentrated under reducedpressure. The residue was crystallized from ether/hexanes to provide theproduct as white crystals (yield: 13 mg, 44.6%). mp 101-103° C. ¹H NMR(300 MHz, CDCl₃) δ 3.05 (s, 3H), 5.40 (s, 2H), 6.95 (t, J=9 Hz, 2H),7.12-7.20 (m, 2H), 7.28-7.41 (m, 3H), 7.31 (d, J=9 Hz, 2H), 7.58-7.53(m, 2H), 7.84 (s, 1H), 7.87 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 435(M+H)⁺. MS (F, high res.) calculated: m/z 435.1179 (M+H)⁺, found: m/z435.1184 (M+H)⁺.

EXAMPLE 6 2-Benzyl-4-(4-fluorophenyl)-5-methoxy-3(2H)-pyridazinone

To a mixture of 2-benzyl-5-methoxy-4-bromo-3(2H)-pyridazinone, preparedaccording to the method of (S. Cho et al. described in J. Het. Chem.,(1996), 33, 1579-1582), (2.94 g; 10 mmol), 4-fluorobenzeneboronic acid(1.54 g; 11 mmol), and CsF (3.04 g; 22 mmol) in 25 mL of anhydrous DME,under N₂, was added Pd(Ph₃P)₄ (347 mg 0.3 mmol). After addition, themixture was heated at reflux for at 100° C., for 18 hours. The mixturewas concentrated in vacuo and the residue partitioned between ethylacetate and water. The acetate layer was washed with brine, dried overMgSO₄ and concentrated in vacuo. The solid residue was suspended inethyl ether-hexanes and filtered to provide a solid product (yield: 3.1g; about 100%; >95% purity). ¹H NMR (300 MHz, CDCl₃) δ 3.90 (s, 3H),5.36 (s, 2H), 7.09 (t, J=9 Hz, 2H), 7.31 (m, 3H), 7.50 (m, 4H), 7.91 (s,1H). MS (DCI/NH₃) m/z 311 (M+H)⁺, 328 (M+NH₄)⁺.

EXAMPLE 7 2-Benzyl-4-(4-fluorophenyl)-5-hydroxy-3(2H)-pyridazinone

The product from Example 6 (1.24 g; 4 mmol) in 20 mL of acetic acid wastreated with aqueous 48% HBr (25 mL). The mixture was heated at refluxfor about 5 to about 8 hours (TLC analysis). The mixture wasconcentrated in vacuo. The product was dissolved in ethyl acetate,washed with 10% bicarbonate, brine and concentrated in vacuo. Theresidue was treated with diethyl ether-hexanes (2:1) and the solid wasfiltered to provide an almost pure product (yield: 1.16 g; 98%). ¹H NMR(300 MHz, DMSO-d₆) δ 5.24 (2H), 7.21 (m, 2H), 7.30 (m, 5H), 7.55 (m,2H), 7.85 (s, 1H), 11.31 (br s, 1H). MS (DCI/NH₃) m/z 296 (M+H)⁺, 314(M+NH₄)⁺.

EXAMPLE 82-Benzyl-4-(4-fluorophenyl)-5-(trifluoromethylsulfonyloxy)-3(2H)-pyridazinone

A solution of the product from Example 7, (89 mg, 0.3 mmol) in 2.5 mL ofanhydrous pyridine under a N₂ atmosphere and maintained at 0° C. wastreated with triflic anhydride (Tf₂O; 0.06 mL; 0.32 mmol) dropwise. Theresulting mixture was stirred at 0° C. for 5 minutes and at roomtemperature for 16 hours. (The pyridine and Tf₂O should be pure for goodresults. Occasionally an additional amount of Tf₂O is necessary to forcethe reaction to completion.) The mixture was then poured to a coldsolution of citric acid and extracted with ethyl acetate to obtain analmost pure product (yield: 127 mg, about 99%). ¹H NMR (300 MHz,DMSO-d₆) δ 5.34 (s, 2H), 7.35 (m, 7H), 7.60 (m, 2H), 8.48 (s, 1H). MS(DCI/NH₃) m/z 429 (M+H)⁺, 446 (M+NH₄)⁺.

EXAMPLE 92-Benzyl-4-(4-fluoro-phenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

A mixture of the product from Example 8 (154 mg, 0.36 mmol),4-(methylthio)benzeneboronic acid (67 mg, 0.4 mmol), Et₃N (0.11 mmol;0.8 mmol) and Pd(Ph₃P)₄ (30 mg, 0.025 mmol) in 15 mL of toluene washeated at reflux, about 100° C. for about 45 minutes. The mixture wasconcentrated in vacuo and the residue purified by column chromatography(hexanes-ethyl acetate 3:1) to provide the title compound (yield: 98 mg,68%). ¹H NMR (300 MHz, CDCl₃) δ 2.47 (s, 3H), 5.38 (s, 2H), 6.98 (m,4H), 7.12 (m, 2H), 7.20 (m, 2H), 7.35 (m, 3H), 7.54 (m, 2H), 7.86 (s,1H). MS (DCI/NH₃) m/z 403 (M+H)⁺, 420 (M+NH₄)⁺.

EXAMPLE 102-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone

To a solution of the product from Example 9 (140 mg, 0.348 mmol), in 10mL of CH₂Cl₂, at 0° C. was added peracetic acid (CH₃COOOH; 0.5 mL; 30%).The mixture was stirred at 0° C. for 90 minutes. The dichloromethane wasthen removed in vacuo. The residue was dissolved in ethyl acetate,washed with 10% NaHCO₃, and brine. The ethyl acetate was removed underreduced pressure. The residue was chromatographed (silica gel,CH₂Cl₂-diethyl ether 19:1) to provide the title compound (yield: 130 mg,86%). ¹H NMR (300 MHz, CDCl₃) δ 3.04 (s, 3H), 5.40 (s, 2H), 6.95 (m,2H), 7.16 (m, 2H), 7.33 (m, 5H), 7.55 (m, 2H), 7.86 (m, 3H). MS(DCI/NH₃) m/z 434 (M+H)⁺, 452 (M+NH₄)⁺.

EXAMPLE 114-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A mixture of the product from Example 10 (37 mg, 0.085 mmol) and AlBr₃(70 mg, 0.26 mmol) in 10 mL of toluene was heated at reflux, about 80°C. for about 15 minutes and cooled to 0° C. The cooled mixture wastreated with 1N HCl and extracted with ethyl acetate. The acetate layerwas washed with water, brine and concentrated in vacuo. Purification ofthe residue on silica gel column (ethyl acetate as an eluent) providedthe title compound (yield: 22 mg, 76%). ¹H NMR (300 MHz, CDCl₃) δ 3.07(s, 3H), 7.00 (t, J=9 Hz, 2H), 7.20 (m, 2H), 7.56 (d, J=9 Hz, 2H), 7.86(s, 1H), 7.91 (d, J=9 Hz, 2H), 10.94 (br s, 1H). MS (DCI/NH₃) m/z 345(M+H)⁺, 362 (M+NH₄)⁺.

EXAMPLE 122-Phenyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 12A 2-Phenyl-4-chloro-5-methoxy-3(2H)-pyridazinone

The title compound was prepared according to the method of (S. Cho etal. described in J. Het. Chem., (1996), 33, 1579-1582), starting withthe N-phenyl-dichloropyridazinone. A mixture of2-phenyl-4,5-dichloro-3(2H)-pyridazinone (1 g, 4.1 mmol) and finelypowdered, anhydrous K₂CO₃ (580 mg, 4.2 mmol) in 50 mL of methanol washeated at reflux for 5 hours and concentrated in vacuo. The residue waspartitioned between water and ethyl acetate. The acetate layer waswashed with water, and brine to provide2-phenyl-4-chloro-5-methoxy-3(2H)-pyridazinone (yield: 920 mg, 95%). ¹HNMR (300 MHz, DMSO-d₆) δ 4.15 (s, 3H), 7.50 (m, 5H), 8.43 (s, 1H). MS(DCI/NH₃) m/z 237 (M+H)⁺, 254 (M+NH₄)⁺.

EXAMPLE 12B 2-Phenyl-4-(4-fluorophenyl)-5-methoxy-3(2H)-pyridazinone

The 2-phenyl-4-chloro-5-methoxy-3(2H)-pyridazinone product was coupledwith 4-fluorophenylboronic acid according to the method of Example 6 toprovide 2-phenyl-4-(4-fluorophenyl)-5-methoxy-3(2H)-pyridazinone (yield:1.1 g; 96%). ¹H NMR (300 MHz, CDCl₃) δ 4.00 (s, 3H), 7.10 (t, J=9 Hz,2H), 7.45 (m, 3H), 7.60 (m, 4H), 8.06 (s, 1H). MS (DCI/NH₃) m/z 297(M+H)⁺.

EXAMPLE 12C 2-Phenyl-4-(4-fluorophenyl)-5-hydroxy-3(2H)-pyridazinone

The 2-phenyl-4-(4-fluorophenyl)-5-methoxy-3(2H)-pyridazinone product wastreated with 48% HBr according to the method of Example 7 to furnish2-phenyl-4-(4-fluorophenyl)-5-hydroxy-3(2H)-pyridazinone (yield: 957 mg,92%). MS (DCI/NH₃) m/z 283 (M+H)⁺, 300 (M+NH₄)⁺.

EXAMPLE 12D2-Phenyl-4-(4-fluorophenyl)-5-trifluoromethanesulfonyloxy-3(2H)-pyridazinone

The 2-phenyl-4-(4-fluorophenyl)-5-hydroxy-3(2H)-pyridazinone product wassulfonylated according to the method of Example 8 to furnish2-phenyl-4-(4-fluorophenyl)-5-trifluoromethanesulfonyloxy-3(2H)-pyridazinone(yield: 1.35 g; 96%) MS (DCI/NH₃) m/z 415 (M+H)⁺, 432 (M+NH₄)⁺.

EXAMPLE 12E2-Phenyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The2-phenyl-4-(4-fluorophenyl)-5-trifluoromethanesulfonyloxy-3(2H)-pyridazinonewas coupled with 4-(methylthio)phenylboronic acid as in Example 9 toprovide2-phenyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(yield: 915 mg, 92%) which was immediately oxidized with peracetic acidas in Example 9 to provide the title compound after columnchromatography (silica gel, 1:1 hexanes-ethyl acetate) andcrystallization from diethyl ether-hexanes (yield: 288 mg, 69%). mp219-220° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.25 (s, 3H), 7.15 (t, J=Hz,2H), 7.30 (m, 2H), 7.46 (m, 1H), 7.56 (m, 4H), 7.64 (m, 2H), 7.90 (d,J=9 Hz, 2H), 8.24 (s, 1H). MS (DCI/NH₃) m/z 421 (M+H)⁺, 438 (M+NH₄)⁺.

EXAMPLE 13 4-Fluorophenylacetic acid, methyl ester

A catalytic amount (0.5 mL) of concentrated sulfuric acid was added to asolution of 4-fluorophenylacetic acid (30.8 g, 0.20 mol) in 500 mL ofmethanol. The solution was stirred at reflux for 4 hours. The volatilematerials were removed under reduced pressure to furnish a colorless oilwhich was dissolved in ether/ethyl acetate and washed with 2 N aqueousNa₂CO₃, brine, dried over MgSO₄, and filtered. The filtrate wasconcentrated under reduced pressure to provide an oil which was driedovernight under high vacuum (yield: 33.6 g; 95%). ¹H NMR (300 MHz,CDCl₃) δ 3.59 (s, 2H), 3.65 (s, 3H), 7.01 (t, J=9 Hz, 2H), 7.20-7.28 (m,2H). MS (DCI/NH₃) m/z 186 (M+NH₄)⁺.

EXAMPLE 14 [4-(Methylthio)phenyl]dimethylthioketene acetal, mono-S-oxide

A mixture of methyl(methylsulfinylmethyl)sulfide (50 g, 0.40 mol), andfinely powdered sodium hydroxide (3.12 g, 0.078 mol) was stirred at 70°C. for 4 hours. 4-(Methylthio)benzaldehyde (27.4 mL, 0.195 mol) was thenadded in one lot and the reaction mixture was stirred at 70° C. for anadditional 4 hours. The mixture was cooled to room temperature andpartitioned between 10% aqueous citric acid and dichloromethane. Theorganic layer was dried over MgSO₄ and filtered. The filtrate wasconcentrated under reduced pressure to provide a brown oil. The oil waspurified by column chromatography (7:3 hexanes/ethyl acetate) to providea solid. The solid was crystallized from ether/hexanes (yield: 24.7 g;72%). mp 52-53° C. ¹H NMR (300 MHz, CDCl₃) δ 2.33 (s, 3H), 2.53 (s, 3H),2.77 (s, 3H), 7.17 (d, J=9 Hz, 2H), 7.57 (s, 1H), 7.86 (d, J=9 Hz, 2H).MS (DCI/NH₃) m/z 259 (M+H)⁺ and m/z 276 (M+NH₄)⁺.

EXAMPLE 152-(4-Fluorophenyl)-3-[4-(methylthio)phenyl]-4-methylthio-4-methylsulfinyl-n-butyricacid methyl ester

A solution of the ester product from Example 13, (16.24 g, 0.0966 mol)in 50 mL of THF was added dropwise to a stirred solution of 1.0 M sodiumhexamethyldisilazide in THF (96.6 mL, 0.0966 mol), maintained at 0° C.,under an atmosphere of dry nitrogen. After 30 minutes, a solution of theketene thioacetal, prepared according to the method of Example 14 (20.8g, 0.0805 mol), in 50 mL of THF, was added dropwise to the reactionmixture maintained at 0° C. After 4 hours, the reaction mixture wasacidified with 10% aqueous citric acid. The aqueous layer was washedtwice with ethyl acetate. The organic extracts were combined, washedwith brine, dried over MgSO₄ and filtered. The filtrate was concentratedunder reduced pressure to provide a brown oil which was purified bycolumn chromatography (85:15 to 1:1 dichloromethane/ethyl acetategradient). Several products having different Rf values and NMR spectrawere isolated. These compounds had identical mass spectra. The mixtureof compounds was carried on in the following reactions (yield: 22.4 g;65%). MS (DCI/NH₃) m/z 444 (M+NH₄)⁺.

EXAMPLE 162-(4-Fluorophenyl)-3-[4-(methylthio)phenyl]-3-formyl-n-propanoic acid,methyl ester

The mixture of compounds from Example 17, (9.0 g, 0.021 mol) weredissolved in acetonitrile (80 mL) and cooled to 0° C. Perchloric acid(60%; 1.06 g, 0.006 mol) was added to the stirred solution. The reactionmixture was stirred at 0° C. for 8 hours, and quenched with 2 N aqueousNa₂CO₃. The acetonitrile was removed under reduced pressure and theresulting aqueous mixture was extracted with ethyl acetate. The organicsolution was dried over MgSO₄ and filtered. The filtrate wasconcentrated under reduced pressure to give a yellow oil which waspurified by column chromatography (silica gel, 7:3 hexanes/ethylacetate). Fractions containing the highest Rf diastereomers from theproduct mixture were concentrated in vacuo and the residue wascrystallized from methanol to furnish the title aldehyde-ester compoundas white crystals (yield: 0.27 g, 4.0%). mp=112-113° C. ¹H NMR (300 MHz,CDCl₃) δ 2.49 (s, 3H), 2.46 (s, 3H), 4.39 (s, 2H), 7.03 (t, J=9 Hz, 1H),7.21 (d, J=9 Hz, 1H), 7.25 (d, J=9 Hz, 2H), 7.40-7.47 (m, 2H). MS(DCI/NH₃) m/z 333 (M+H)⁺ and m/z 350 (M+NH₄)⁺. Fractions containinglower R^(f) compounds from the product mixture were concentrated invacuo and the residue was identified as the hydrate of thealdehyde-ester (yield: 2.6 g, 35.2%). ¹H NMR (300 MHz, CDCl₃) δ 2.44 &2.46 (2 s, 3H), 3.56 & 3.48 (2 s, 3H), 3.55 & 3.76 (2 dd, J=6 Hz, J=6Hz, 1H), 3.98 & 4.26 (2 d, J=12 Hz, 1H), 5.41 & 5.47 (2 d, J=6 Hz, 1H),6.96 & 7.00 (t, J=9 Hz, 2H), 7.11-7.26 (m, 6H). MS (DCI/NH₃) m/z 333(M+H)⁺ and m/z 350 (M+NH₄)⁺.

The lowest Rf compound was identified as the hydroxy lactone formed whena hydroxy group from the hydrate displaces the methoxy group from theester (yield: 1.1 g, 16.4%). ¹H NMR (300 MHz, CDCl₃) δ 2.45 (s, 3H),3.54-3.71 (m, 1H), 3.98-4.21 (m, 1H), 4.61 (br s, 1H), 5.85-6.01 (m,1H), 6.98 (t, J=9 Hz, 2H), 7.12-7.27 (m, 6H). MS (DCI/NH₃) m/z 336(M+NH₄)⁺.

EXAMPLE 174-(4-Fluorophenyl)-5-[4-(methylthio)phenyl]-4,5-dihydro-3(2H)-pyridazinone

The aldehyde-ester, hydrate, and hydroxy lactone from Example 16 (0.10g, 3 mmol), were dissolved in 100 mL of ethanol. This solution wastreated with hydrazine monohydrate (0.15 mL, 30 mmol) and the resultingsolution was stirred at reflux in a Soxhelet apparatus containingmolecular sieves. After 18 hours, the reaction mixture was cooled andthe volatile materials removed under reduced pressure. The residue waspartitioned between ethyl acetate and aqueous HCl. The aqueous layer waswashed twice with ethyl acetate. The combined organic extracts werewashed twice with brine, dried over MgSO₄, and filtered. The filtratewas concentrated under reduced pressure and the residue was purified bycolumn chromatography (4:1 hexanes/ethyl acetate) to obtain the titlecompound (yield: 50 mg, 53%). ¹H NMR (300 MHz, CDCl₃) δ 2.46 (s, 3H),3.75 (d, J=12 Hz, 1H), 3.87 (d, J=12 Hz, 1H), 6.93-7.08 (m, 6H), 7.16(d, J=9 Hz, 2H), 8.71 (s(br), 1H). MS (DCI/NH₃) m/z 315 (M+H)⁺ and m/z332 (M+NH₄)⁺.

EXAMPLE 184-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4,5-dihydro-3(2H)-pyridazinone

A solution of peracetic acid, 32% in acetic acid, (0.4 mL, 1.6 mmol) wasadded to a stirred solution of the sulfide from Example 17 (0.050 g,0.16 mmol) in dichloromethane, and maintained at 0° C. The reactionmixture was stirred for 5 hours at 0° C. then diluted with water. Theorganic layer was dried over MgSO₄ and filtered. The filtrate wasconcentrated under reduced pressure to provide an oil which solidifiedon trituration with ether (yield: 47 mg, 85%). ¹H NMR (300 MHz, CDCl₃) δ3.05 (s, 3H), 3.77 (d, J=12 Hz, 1H), 4.05 (d, J=12 Hz, 1H), 6.95-7.08(m, 4H), 7.28 (d, J=9 Hz, 2H), 7.90 (d, J=9 Hz, 2H), 8.75 (s, broad,1H). MS (DCI/NH₃) m/z 364 (M+NH₄)⁺.

EXAMPLE 194-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The dihydropyridazinone product from Example 18 (47 mg, 0.136 mmol) wasdissolved in acetic acid (25 mL). Bromine (0.025 mL, 0.16 mmol) wasadded to the solution and the reaction mixture was stirred at 95° C. for20 minutes. The reaction mixture was concentrated under reducedpressure. The residue was partitioned between ethyl acetate and water.The organic layer was washed with brine, dried over MgSO₄ and filtered.The filtrate was concentrated under reduced pressure to provide a solidwhich was eluted through a short pad of silica gel with ethyl acetate.The title compound was crystallized from ethyl acetate/hexanes (yield:35 mg, 75%). mp 255-256° C. ¹H NMR (300 MHz, CDCl₃) δ 3.07 (s, 3H), 6.98(t, J=9 Hz, 2H), 7.16-7.23 (m, 2H), 7.35 (d, J=9 Hz, 2H), 7.86 (s, 1H),7.91 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 345 (M+H)⁺ and m/z 362 (M+NH₄)⁺.

EXAMPLE 202-(4-Fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A solution of the nitrogen-unsubstituted pyridazinone product fromExample 19 (160 mg, 0.465 mmol), K₂CO₃ (193 mg, 1.4 mmol),4-fluorobenzylbromide (0.09 mL, 0.7 mmol) and NaI (catalytic) in 10 mLof anhydrous N,N-dimethylformamide (DMF) was stirred at room temperaturefor 18 hours. The reaction mixture was quenched with 2N HCl, extractedwith ethyl acetate (2×20 mL), washed with brine and water, dried overMgSO₄, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (2:2:6 ethyl acetate/dichloromethane/pentanes).Crystallization from ether/pentanes provided white crystals (yield: 110mg, 52%). mp 153-154° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.06 (s, 3H), 5.36(s, 2H), 6.96 (t, J=8.4 Hz, 2H), 7.04 (t, J=8.7 Hz, 2H), 7.16 (dd, J=9.1Hz, J=5.4 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 7.54 (dd, J=8.8 Hz, 5.5 Hz,2H), 7.84 (s, 1H), 7.87 (d, J=8.8 Hz, 2H). MS (DCI/NH₃) m/z 453 (M+H)⁺.

EXAMPLE 212-(Phenylpropargyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting phenylpropargyl bromide for 4-fluorobenzyl bromide. mp100-103° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.06 (s, 3H), 5.26 (s, 2H), 6.97(t, J=9 Hz-2H), 7.20 (dd, J=9 Hz, J=6 Hz, 2H), 7.31 (m, 3H), 7.34 (d,J=9 Hz, 2H), 7.48 (m, 2H), 7.89 (d, J=9 Hz, 2H), 7.9 (s, 1H). MS(DCI/NH₃) m/z 459 (M+H)⁺.

EXAMPLE 222-(2,4-Difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2,4-difluorobenzyl bromide for 4-fluorobenzyl bromide. mp179-182° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.06 (s, 3H), 5.45 (s, 2H), 6.87(m, 2H), 6.96 (t, J=9 Hz, 2H), 7.17 (dd, J=9 Hz, J=6 Hz, 2H), 7.32 (d,J=9 Hz, 2H), 7.54 (m, 1H), 7.86 (s, 1H), 7.88 (d, J=9 Hz, 2H). MS(DCI/NH₃) m/z 471 (M+H)⁺.

EXAMPLE 232-(Methyl-2-propenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 3-chloro-2-methylpropene for 4-fluorobenzyl bromide. mp140-142° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.86 (s, 3H), 3.08 (s, 3H), 4.83(s, 2H), 4.94 (t, J=1 Hz, 1H), 5.05 (t, J=1 Hz, 1H), 6.98 (t, J=9 Hz,2H), 7.21 (dd, J=9 Hz, J=6 Hz, 2H), 7.37 (d, J=9 Hz, 2H), 7.89 (s, 1H),7.91 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 399 (M+H)⁺.

EXAMPLE 242-(3-Methyl-2-butenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The desired compound was prepared according to the method of Example 20substituting 4-bromo-2-methyl-2-butene for 4-fluorobenzyl bromide. mp169-172° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.78 (s, 3H), 1.85 (s, 3H), 3.06(s, 3H), 4.86 (d, J=7.5 Hz, 2H), 5.47 (t, J=7.5 Hz, 1H), 6.96 (t, J=9Hz, 2H), 7.18 (dd, J=9 Hz, J=6 Hz, 2H), 7.33 (d, J=9 Hz, 2H), 7.84 (s,1H), 7.88 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 413 (M+H)⁺.

EXAMPLE 252-(2-Trifluoromethylbenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2-(trifluoromethyl)benzyl bromide for 4-fluorobenzylbromide. mp 87-90° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.07 (s, 3H), 5.66 (s,2H), 6.97 (t, J=9 Hz, 2H), 7.21 (dd, J=9 Hz, J=6 Hz, 2H), 7.26 (d, J=7.7Hz, 1H), 7.37 (d, J=9 Hz, 2H), 7.42 (t J=7.7 Hz, 1H), 7.53 (t, J=7.7 Hz,1H), 7.73 (d J=7.7 Hz, 1H), 7.9 (s, 1H), 7.91 (d, J=9 Hz, 2H). MS(DCI/NH₃) m/z 503 (M+H)⁺.

EXAMPLE 262-(Cyclopropylmethyl)-4-(4-fluoro-phenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2-(bromomethyl)cyclopropane for 4-fluorobenzyl bromide. mp118-121° C. ¹H NMR (CDCl₃, 300 MHz) δ 0.45-0.52 (m, 2H), 0.54-0.63 (m,2H), 1.40-1.52 (m, 1H), 3.07 (s, 3H), 4.07 (d, J=7 Hz, 2H), 6.97 (t, J=9Hz, 2H), 7.19 (dd, J=9 Hz, J=6 Hz, 2H), 7.35 (d, J=9 Hz, 2H), 7.83 (s,1H), 7.88 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 399 (M+H)⁺ and m/z 416(M+NH₄)⁺.

EXAMPLE 272-(2-Pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2-(bromomethyl)pyridine for 4-fluorobenzyl bromide. mp182-184° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.07 (s, 3H), 5.56 (s, 2H), 6.95(m, 2H), 7.17 (m, 2H), 7.26 (m, 1H), 7.35 (m, 2H), 7.46 (m, 1H), 7.71(m, 1H), 7.90 (m, 3H), 8.63 (m, 1H). MS (DCI/NH₃) m/z 436 (M+H)⁺.

EXAMPLE 282-(4-Pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 4-(bromomethyl)pyridine for 4-fluorobenzyl bromide. mp153-156° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.07 (s, 3H), 5.40 (s, 2H), 6.97(m, 2H), 7.17 (m, 2H), 7.34 (m, 2H), 7.42 (m, 2H), 7.90 (m, 3H), 8.63(m, 2H). MS (DCI/NH₃) m/z 436 (M+H)⁺.

EXAMPLE 292-(3-Pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 3-(bromomethyl)pyridine for 4-fluorobenzyl bromide. mp160-161° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.07 (s, 3H), 5.43 (s, 2H), 6.97(m, 2H), 7.15 (m, 2H), 7.34 (m, 4H), 7.35 (m, 2H), 7.87 (m, 2H), 7.97(s, 1H), 8.60 (m, 1H), 8.81 (m, 1H). MS (DCI/NH₃) m/z 436 (M+H)⁺.

EXAMPLE 302-(6-Fluoroquinolin-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2-(chloromethyl)-6-fluoroquinoline for 4-fluorobenzylbromide. mp 116-119° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.07 (s, 3H), 5.73 (s,2H), 6.96 (m, 2H), 7.18 (m, 2H), 7.34 (m, 4H), 7.35 (m, 2H), 7.46 (m,2H), 7.58 (m, 3H), 7.90 (m, 3H), 8.12 (m, 2H). MS (DCI/NH₃) m/z 504(M+H)⁺.

EXAMPLE 312-(Quinolin-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2-(chloromethyl)-quinoline for 4-fluorobenzyl bromide. mp97-100° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.06 (s, 3H), 5.75 (s, 2H), 6.95(m, 2H), 7.19 (m, 2H), 7.35 (m, 2H), 7.55 (m, 2H), 7.73 (m, 1H), 7.82(m, 1H), 7.90 (m, 3H), 8.15 (m, 2H). MS (DCI/NH₃) m/z 386 (M+H)⁺.

EXAMPLE 322-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinethione

A mixture of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone,prepared according to the method of Example 5, (109 mg, 0.25 mmol) andLawesson's reagent (202 mg, 0.5 mmol) in 15 mL of toluene was stirred atreflux for 48 hours. The mixture was concentrated in vacuo and theresidue was chromatographed (silica gel, ethyl acetate) to provide thetitle compound (yield: 100 mg, 88%). mp 88-90° C. ¹H NMR (300 MHz,CDCl₃) δ 3.04 (s, 3H), 6.05 (s, 2H), 6.96 (m, 2H), 7.08 (m, 2H), 7.26(m, 2H), 7.37 (m, 3H), 7.61 (m, 2H), 7.84 (d, J=9 Hz, 2H), 8.13 (s, 1H).MS (DCI/NH₃) m/z 451 (M+H)⁺.

EXAMPLE 332-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

Example 33 was prepared using a similar procedure as that described in(M. De Vleeschauwer and J. V. Gauthier, Syn. Lett., (1997) 375).

EXAMPLE 33A2-Benzyl-4(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone

A solution of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,prepared according to the method of Example 4, (450 mg, 1.12 mmol) inCH₂Cl₂ (10 mL) was added dropwise to a suspension ofhydroxy(tosyloxy)iodobenzene (439 mg, 1.12 mmol) in CH₂Cl₂ (15 mL) andthe mixture was stirred until a clear solution was obtained (about 1hour). The reaction mixture was then washed with water and dried withMgSO₄. Removal of solvent in vacuo provided the corresponding sulfoxide(yield: 485 mg, about 100%). ¹H NMR (300 MHz, CDCl₃) δ 2.72 (s, 3H),5.40 (s, 2H), 6.90 (m, 2H), 7.15 (m, 3H), 7.33 (m, 3H), 7.57 (m, 3H),7.71 (m, 1H), 7.86 (s, 1H). MS (DCI/NH₃) m/z 419 (M+H)⁺, 436 (M+NH₄)⁺.

EXAMPLE 33B2-benzyl-4-(4-fluorophenyl)-5-(acetoxymethylsulfonylphenyl)-3(2H)-pyridazinone

A suspension of the sulfoxide from Example 33A, (485 mg, 1.12 mmol) andAcONa (1.4 g) in 15 mL of Ac₂O was stirred at reflux for 2 hours andconcentrated in vacuo. The residue was distilled twice with toluene,dissolved in 25 mL of CH₂Cl₂, cooled to 0° C., and treated with CH₃CO₃H(1 mL). After 1 hour, the mixture was washed, successively, withsaturated NaHCO₃ and brine. The solvent was removed in vacuo. Theresidue was chromatographed (silica gel, 1:1 hexanes-ethyl acetate) toprovide the desired product,2-benzyl-4-(4-fluorophenyl)-5-(acetoxymethylsulfonylphenyl)-3(2H)-pyridazinone(yield: 150 mg, 27%). MS (DCI/NH₃) m/z 493 (M+H)⁺.

EXAMPLE 33C2-Benzyl-4-(4-fluorophenyl)-5-[4-(sodiumsulfinate)phenyl]-3(2H)-pyridazinone

To a solution of the acetoxymethylsulfone from Example 33B (150 mg,0.305 mmol), in 10 mL of THF and 5 mL of methanol at 0° C., was added 1N NaOH (0.305 mL, 0.305 mmol). The mixture was stirred at 0° C. for 1hour. The mixture was concentrated in vacuo, the residual water wasremoved via an EtOH/toluene azeotrope followed by a toluene azeotrope.The residue was dried under high vacuum for 48 hours to provide thesodium sulfinate (yield: 140 mg, 96%). MS (DCI/NH₃) M/Z 443 (M+H)⁺

EXAMPLE 33D2-Benzyl-4-(4-fluorophenyl)-5-[4-(chlorosulfonyl)phenyl]-3(2H)-pyridazinone

The sodium sulfinate (about 0.31 mmol) in CH₂Cl₂ (10 mL) was treated at0° C. with SOCl₂ (0.033 mL, 0.4 mmol) for 2 hours. The mixture waswashed with brine, dried with MgSO₄ and concentrated in vacuo to providethe crude sulfonyl chloride (yield: 145 mg, about 100%). MS (DCI/NH₃)m/z 455 (M+H)⁺.

EXAMPLE 33E2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The crude chloride prepared according to the method of Example 33D, in10 mL of THF, was added to a solution of 50% NH₄OH, in 10 mL of THF,maintained at 0° C. The mixture was allowed to warm to room temperatureover 3.5 hours. The THF was removed in vacuo and the product wasextracted with ethyl acetate. The ethyl acetate was removed in vacuo andthe residue was treated with diethyl ether-hexanes 2:1 to provide thesulfonamide (yield: 113 mg, 84%). mp 188-191° C. ¹H NMR (300 MHz,DMSO-d₆) δ 2.70 (dd, J=15 Hz, 2H), 5.36 (s, 2H), 7.13 (t, J=9 Hz, 2H),7.22 (m, 2H), 7.40 (m, 7H), 7.73 (d, J=9 Hz, 2H), 8.11 (s, 1H). MS(DCI/NH₃) m/z 436 (M+H)⁺.

EXAMPLE 342-(2,2,2-Trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone

The title compound was prepared according to the method of Example 20substituting 2-iodo-1,1,1-trifluoroethane for 4-fluorobenzyl bromide. mp177-179° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.06 (s, 3H), 4.88 (q, J=9 Hz,2H), 6.98 (t, J=9 Hz, 2H), 7.18 (dd, J=9 Hz, J=6 Hz, 2H), 7.35 (d, J=9Hz, 2H), 7.89 (s, 1H), 7.91 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 427 (M+H)⁺and m/z 444 (M+N₄)⁺.

EXAMPLE 352-(3,3-Dichloro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 1,1,3-trichloropropene for 4-fluorobenzyl bromide. mp150-152° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.06 (s, 3H), 4.98 (d, J=7 Hz,2H), 6.25 (t, J=7 Hz, 1H), 6.98 (t, J=9 Hz, 2H), 7.18 (dd, J=9 Hz, J=6Hz, 2H), 7.33 (d, J=9 Hz, 2H), 7.85 (s, 1H), 7.89 (d, J=9 Hz, 2H). MS(DCI/NH₃) m/z 453 (M+H)⁺ and m/z 470 (M+NH₄)⁺.

EXAMPLE 362-(3-Phenyl-2-propenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting cinnamyl bromide for 4-fluorobenzyl bromide. mp 165-167° C.¹H NMR (CDCl₃, 300 MHz) δ 3.06 (s, 3H), 5.01 (d, J=7 Hz, 2H), 6.48 (dt,J=15 Hz, 7 Hz, 1H), 6.79 (d, J=15 Hz, 1H), 6.97 (t, J=9 Hz, 2H), 7.19(dd, J=9 Hz, J=6 Hz, 2H), 7.25-7.44 (m, 5H), 7.37 (d, J=9 Hz, 2H), 7.86(s, 1H), 7.89 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 461 (M+H)⁺ and m/z 478(M+NH₄)⁺.

EXAMPLE 372-(4-Carboxyphenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting methyl 4-(bromomethyl)benzoate for 4-fluorobenzyl bromideand hydrolysis of the resulting ester. mp 239-241° C. ¹H NMR (CDCl₃, 300MHz) δ 3.06 (s, 3H), 5.46 (s, 2H), 6.96 (t, J=9 Hz, 2H), 7.17 (dd, J=9Hz, 6 Hz, 2H), 7.33 (d, J=9 Hz, 2H), 7.63 (d, J=9 Hz, 2H), 7.87 (s, 1H),7.89 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 479 (M+H)⁺and m/z 496 (M+NH₄)⁺.

EXAMPLE 382-(5-Methylthiazol-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2-(bromomethyl)-5-methylthiazole for 4-fluorobenzylbromide. mp 114-116° C. ¹H NMR (d₆-DMSO, 300 MHz) δ 2.64 (s, 3H), 3.23(s, 2H), 5.37 (s, 2H), 7.13 (m, 2H), 7.23 (m, 2H), 7.40 (s, 1H), 7.47(d, J=8 Hz, 2H), 7.87 (d, J=8 Hz, 2H), 8.10 (s, 1H). MS (DCI/NH₃) m/z356 (M+H)⁺.

EXAMPLE 392-(5-Chlorothiazol-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2-(bromomethyl)-5-chlorothiazole for 4-fluorobenzylbromide. mp 185-186° C. ¹H NMR (d₆-DMSO, 300 MHz) δ 2.32 (s, 3H), 5.50(s, 2H), 7.15 (m, 2H), 7.24 (m, 2H), 7.47 (m, 2H), 7.87 (m, 3H), 8.14(s, 1H). MS (DCI/NH₃) m/z 476 (M+H)⁺ and m/z 493 (M+NH₄)⁺.

EXAMPLE 402-(2,3,3,4,4,4-Hexafluorobuten-1-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2,2,3,3,4,4,4-heptafluoro-1-iodobutane for 4-fluorobenzylbromide. Under the alkylation conditions, elimination of HF provided theunsaturated product. mp 167-169° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.07 (s,3H), 7.00 (t, J=9 Hz, 2H), 7.17 (dd, J=9 Hz, 6 Hz, 2H), 7.33 (d, J=9 Hz,2H), 7.68 (d, J=24 Hz, 1H), 7.93 (d, J=9 Hz, 2H), 8.01 (s, 1H). MS(DCI/NH₃) m/z 507 (M+H)⁺ and m/z 524 (M+NH₄)⁺.

EXAMPLE 412-(2,4-Difluorophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2-chloro-2′,4′-difluoroacetophenone for 4-fluorobenzylbromide. mp 191-192° C. ¹H NMR (CDCl₃, 300 MHz) δ 3.08 (s, 3H), 5.57 (d,J=3 Hz, 2H), 6.94-7.07 (m, 2H), 6.96 (t, J=9 Hz, 2H), 7.39 (dd, J=9 Hz,6 Hz, 2H), 7.91 (s, 1H), 7.91 (d, J=9 Hz, 2H), 8.03-8.12 (m, 1H). MS(DCI/NH₃) m/z 499 (M+H)⁺ and m/z 516 (M+NH₄)⁺.

EXAMPLE 422-(5-Chlorothien-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2-(bromomethyl)-5-chlorothiophene for 4-fluorobenzylbromide. mp 139-141° C. ¹H NMR (d₆-DMSO, 300 MHz) δ 3.23 (s, 3H), 5.43(s, 2H), 7.03 (d, J=4 Hz, 1H), 7.09-7.29 (m, 5H), 7.47 (d, J=8 Hz, 2H),7.87 (d, J=8 Hz, 3H), 8.13 (s, 1H). MS (DCI/NH₃) m/z 474 (M+H)⁺ and m/z492 (M+NH₄)⁺.

EXAMPLE 432-(5-Methylthien-2-Ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2-(bromomethyl)-5-methylthiophene for 4-fluorobenzylbromide. mp 172-175° C. ¹H NMR (d₆-DMSO, 300 MHz) δ 3.22 (s, 3H), 5.49(s, 2H), 7.03 (m, 1H), 7.14 (m, 2H), 7.23 (m, 3H), 7.48 (m, 3H), 7.86(m, 2H), 8.11 (s, 1H). MS (DCI/NH₃) m/z 441 (M+H)⁺ and m/z 458 (M+NH₄)⁺.

EXAMPLE 442-(4-Diethylaminophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2-chloro-4′-dimethylaminoacetophenone for 4-fluorobenzylbromide. mp 105-108° C. ¹H NMR (CDCl₃, 300 MHz) δ 1.23 (t, J=7 Hz, 3H),3.07 (s, 3H), 3.44 (q, J=7 Hz, 2H), 5.61 (s, 2H), 6.66 (d, J=9 Hz, 2H),6.94 (t, J=9 Hz, 2H), 7.21 (dd, J=9 Hz, 6 Hz, 2H), 7.38 (d, J=9 Hz, 2H),7.87-7.94 (m, 4H), 7.90 (s, 1H). MS (DCI/NH₃) m/z 534 (M+H)⁺.

EXAMPLE 452-(2,3,4,5,6-Pentafluorobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2,3,4,5,6-pentafluorobenzyl bromide for 4-fluorobenzylbromide. mp 115-116° C. ¹H NMR (CDCl₃, 300 MHz) 3.06 (s, 3H), 5.50 (s,2H), 6.96 (t, J=9 Hz, 2H), 7.17 (dd, J=9 Hz, 6 Hz, 2H), 7.33 (d, J=9 Hz,2H), 7.82 (s, 1H), 7.89 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 525 (M+H)⁺ andm/z 542 (M+NH₄)⁺.

EXAMPLE 462-(Phenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2-bromoacetophenone for 4-fluorobenzyl bromide. mp 228-230°C. ¹H NMR (CDCl₃, 300 MHz) 3.07 (s, 3H), 5.68 (s, 2H), 6.95 (t, J=9 Hz,2H), 7.20 (dd, J=9 Hz, 6 Hz, 2H), 7.38 (d, J=9 Hz, 2H), 7.53 (t, J=7 Hz,2H), 7.65 (t, J=7 Hz, 1H), 7.90 (d, J=9 Hz, 2H), 7.91 (s, 1H), 8.04 (d,J=7 Hz, 2H). MS (DCI/NH₃) m/z 463 (M+H)⁺ and m/z 480 (M+NH₄)⁺.

EXAMPLE 472-(4-Chlorophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2-bromo-4′-chloroacetophenone for 4-fluorobenzyl bromide.mp 186-188° C. ¹H NMR (CDCl₃, 300 MHz) 3.07 (s, 3H), 5.63 (s, 2H), 6.95(t, J=9 Hz, 2H), 7.19 (dd, J=9 Hz, 6 Hz, 2H), 7.38 (d, J=9 Hz, 2H), 7.51(d, J=9 Hz, 2H), 7.65 (t, J=7 Hz, 1H), 7.90 (d, J=9 Hz, 2H), 7.91 (s,1H), 7.98 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 497 (M+H)⁺ and m/z 514(M+NH₄)⁺.

EXAMPLE 482-(Propargyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting propargyl bromide for 4-fluorobenzyl bromide. mp 196-198°C. ¹H NMR (CDCl₃, 300 MHz) 2.42 (t, J=3 Hz, 1H), 3.06 (s, 3H), 5.04 (d,J=3 Hz, 2H), 6.97 (t, J=9 Hz, 2H), 7.19 (dd, J=9 Hz, 6 Hz, 2H), 7.34 (d,J=9 Hz, 2H), 7.90 (s, 1H), 7.91 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 383(M+H)⁺ and m/z 400 (M+NH₄)⁺.

EXAMPLE 492-(4-Cyanophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2-bromo-4′-cyanoacetophenone for 4-fluorobenzyl bromide. mp188-189° C. ¹H NMR (CDCl₃, 300 MHz) 3.08 (s, 3H), 5.64 (s, 2H), 6.96 (t,J=9 Hz, 2H), 7.19 (dd, J=9 Hz, 6 Hz, 2H), 7.38 (d, J=9 Hz, 2H), 7.84 (d,J=9 Hz, 2H), 7.91 (d, J=9 Hz, 2H), 7.93 (s, 1H), 8.14 (d, J=9 Hz, 2H).MS (DCI/NH₃) m/z 488 (M+H)⁺.

EXAMPLE 502-(α-Methyl-4-fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting α-methyl-4-fluorobenzyl bromide for 4-fluorobenzyl bromide.mp 162-164° C. ¹H NMR (CDCl₃, 300 MHz) 3.06 (s, 3H), 6.40 (t, J=9 Hz,2H), 6.95 (t, J=9 Hz, 2H), 7.05 (t, J=9 Hz, 2H), 7.15 (dd, J=9 Hz and 6Hz, 2H), 7.31 (d, J=9 Hz, 2H), 7.53 (dd, J=9 Hz and 6 Hz, 2H), 7.87 (d,J=9 Hz, 2H), 7.88 (s, 1H). MS (DCI/NH₃) m/z 467 (M+H)⁺ and m/z 484(M+NH₄)⁺.

EXAMPLE 512-Phenethyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting (2-bromoethyl)benzene for 4-fluorobenzyl bromide. mp170-171° C. ¹H NMR (CDCl₃, 300 MHz) 3.07 (s, 3H), 3.20 (t, J=9 Hz, 2H),4.28 (t, J=9 Hz, 2H), 6.98 (t, J=9 Hz, 2H), 7.18 (dd, J=9 Hz and 6 Hz,2H), 7.22-37 (m, 5H), 7.34 (d, J=9 Hz, 2H), 7.83 (s, 1H), 7.89 (d, J=9Hz, 2H). MS (DCI/NH₃) m/z 449 (M+H)⁺ and m/z 466 (M+NH₄)⁺.

EXAMPLE 522-Benzyl-4-(3-chloro-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method described inExamples 6-10 substituting 3-chloro-4-fluorobenzeneboronic acid for4-fluorobenzeneboronic acid in Example 6. mp 134-136° C. ¹H NMR (CDCl₃,300 MHz) 3.06 (s, 3H), 5.41 (s, 2H), 6.96-7.02 (m, 2H), 7.29-7.41 (m,3H), 7.33 (d, J=9 Hz, 2H), 7.51-7.56 (m, 2H), 7.85 (s, 1H), 7.91 (d, J=9Hz, 2H). MS (DCI/NH₃) m/z 469 (M+H)⁺ and m/z 486 (M+NH₄)⁺.

EXAMPLE 532-Benzyl-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method described inExamples 6-10 except substituting 4-chlorobenzeneboronic acid for4-fluorobenzeneboronic acid in Example 6. mp 157-159° C. ¹H NMR (CDCl₃,300 MHz) 3.05 (s, 3H), 5.40 (s, 2H), 7.11 (d, J=9 Hz, 2H), 7.24 (d, J=9Hz, 2H), 7.28-7.40 (m, 2H), 7.31 (d, J=9 Hz, 2H), 7.51-7.57 (m, 2H),7.84 (s, 1H), 7.88 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 451 (M+H)⁺ and m/z468 (M+NH₄)⁺.

EXAMPLE 542-(2,2,2-Trifluoroethyl)-4-(3-chloro-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared by N-debenzylation of the product,prepared in Example 52 according to the method of Example 11, followedby alkylation with 2-iodo-1,1,1-trifluoroethane according to the methodof Example 20. mp 165-166° C. ¹H NMR (CDCl₃, 300 MHz) 3.07 (s, 3H), 4.89(q, J=9 Hz, 2H), 7.00-7.06 (m, 2H), 7.31-7.35 (m, 1H), 7.37 (d, J=9 Hz,2H), 7.90 (s, 1H), 7.94 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 461 (M+H)⁺ andm/z 478 (M+NH₄)⁺.

EXAMPLE 552-(4-Trifluoromethoxyphenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2-bromo-4′-trifluoromethoxyacetophenone for 4-fluorobenzylbromide. mp 160-161° C. ¹H NMR (CDCl₃, 300 MHz) 3.08 (s, 3H), 5.65 (s,2H), 6.96 (t, J=9 Hz, 2H), 7.20 (dd, J=9 Hz, 6 Hz, 2H), 7.37 (d, J=9 Hz,2H), 7.91 (d, J=9 Hz, 2H), 7.93 (s, 1H), 8.11 (d, J=9 Hz, 2H). MS(DCI/NH₃) m/z 547 (M+H)⁺ and m/z 564 (M+NH₄)⁺.

EXAMPLE 562-(4-Trifluoromethylphenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 2-bromo-4′-trifluoromethylacetophenone for 4-fluorobenzylbromide. mp 205-206° C. ¹H NMR (CDCl₃, 300 MHz) 3.07 (s, 3H), 5.66 (s,2H), 6.96 (t, J=9 Hz, 2H), 7.20 (dd, J=9 Hz, 6 Hz, 2H), 7.38 (d, J=9 Hz,2H), 7.80 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz, 2H), 7.92 (s, 1H), 8.15 (d,J=9 Hz, 2H). MS (DCI/NH₃) m/z 531 (M+H)⁺ and m/z 548 (M+NH₄)⁺.

EXAMPLE 572-[2-(Benzo[b]thien-3-yl)-2-oxoethyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 3-chloroacetylbenzo[b]thiophene for 4-fluorobenzyl bromide.mp 183-184° C. ¹H NMR (CDCl₃, 300 MHz) 3.08 (s, 3H), 5.68 (s, 2H), 6.96(t, J=9 Hz, 2H), 7.21 (dd, J=9 Hz, 6 Hz, 2H), 7.39 (d, J=9 Hz, 2H),7.42-7.54 (m, 2H), 7.91 (d, J=9 Hz, 2H), 7.91 (d, J=7 Hz, 1H), 7.94 (s,1H), 8.53 (s, 1H), 8.72 (d, J=7 Hz, 1H). MS (DCI/NH₃) m/z 519 (M+H)⁺.

EXAMPLE 582-(2,2,2-Trifluoroethyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared by N-debenzylation of the product,prepared in Example 53 according to the method of Example 12, followedby alkylation with 2-iodo-1,1,1-trifluoroethane according to the methodof Example 20. mp 55-57° C. ¹H NMR (CDCl₃, 300 MHz) 3.07 (s, 3H), 4.88(q, J=9 Hz, 2H), 7.13 (d, J=9 Hz, 2H), 7.26 (d, J=9 Hz, 2H), 7.36 (d,J=9 Hz, 2H), 7.89 (s, 1H), 7.92 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 443(M+H)⁺ and m/z 460 (M+NH₄)⁺.

EXAMPLE 592-(3,3-Dimethyl-2-oxobutyl)-4(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 1-bromopinacolone for 4-fluorobenzyl bromide. mp 168-170°C. ¹H NMR (CDCl₃, 300 MHz) 1.31 (s, 9H), 3.06 (s, 3H), 5.21 (s, 2H),6.95 (t, J=9 Hz, 2H), 7.17 (dd, J=9 Hz, 6 Hz, 2H), 7.35 (d, J=7 Hz, 2H),7.86 (s, 1H) 7.89 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 443 (M+H)⁺ and m/z460 (M+NH₄)⁺.

EXAMPLE 602-(3-Thienylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 3-(chloromethyl)thiophene for 4-fluorobenzyl bromide. mp169-172° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.22 (s, 3H), 5.36 (s, 2H), 7.18(m, 5H), 7.51 (m, 4H), 7.88 (m, 2H); 8.08 (s, 1H). MS (DCI/NH₃) m/z 441(M+H)⁺ and m/z 458 (M+NH₄)⁺.

EXAMPLE 612-(2-Benzo[b]thienylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20substituting 2-(chloromethyl)benzo[b]thiophene for 4-fluorobenzylbromide. mp 93-96° C. ¹H NMR (300 MHz, CDCl₃) δ 3.05 (s, 3H), 5.64 (s,2H), 6.97 (m, 2H), 7.18 (m, 2H), 7.33 (m, 5H), 7.78 (m, 2H), 7.86 (m,3H). MS (DCI/NH₃) m/z 491 (M+H)⁺ and m/z 508 (M+NH₄)⁺.

EXAMPLE 622,4-Bis(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A mixture of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (172mg, 0.5 mmol), prepared according to the method of Example 10, Cu powder(32 mg), anhydrous K₂CO₃ (207 mg, 1.5 mmol) and 4-fluoroiodobenzene(0.12 mL, 1 mmol) was prepared in 20 mL of pyridine. The solution wasstirred at reflux for 14 hours. The mixture was then cooled to roomtemperature and partitioned between water and ethyl acetate. The ethylacetate layer was washed with 10% citric acid, water, brine andconcentrated in vacuo. Separation by column chromatography (silica gel,CH₂Cl₂-diethyl ether 15:1) provided 190 mg of crude product.Crystallization from CH₂Cl₂-diethyl ether-hexanes furnished the titlecompound (yield: 175 mg, 79.9%). mp 168-169° C. ¹H NMR (300 MHz, CDCl₃)δ 3.07 (s, 3H), 6.98 (t, J=9 Hz, 2H), 7.20 (m, 4H), 7.40 (d, J=9 Hz,2H), 7.69 (m, 2H), 7.92 (d, J=9 Hz, 2H), 7.98 (s, 1H). MS (DCI/NH₃) m/z439 (M+H)⁺, 456 (M+NH4)⁺. Anal. calc. for C₂₃H₁₆F₂N₂O₃S.0.25H₂O: C,62.36; H, 3.75; N, 6.32. Found: C, 62.23; H, 3.55; N, 6.26.

EXAMPLE 634-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-6-methyl-3(2H)-pyridazinone

The 5-hydroxy-5-methyl-2(5H)-furanone prepared via above cited methods(454 mg, 1.25 mmol) was dissolved in n-butanol (10 mL) and treated withhydrazine hydrate (0.3 mL, 6.2 mmol) and stirred at reflux for 18 hours.On cooling, white crystals (224 mg, 50%) were obtained. mp 290° C.(dec.) 1 (300 MHz, d₆-DMSO) δ 1.99 (s, 3H), 3.10 (s, 3H), 7.05 (t, J=9Hz, 2H), 7.15 (dd, J=6 Hz, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 2H), 7.85 (d,J=9 Hz, 2H), 13.10 (br s, 1H). MS (DCI/NH₃) 376 (M+NH₄)⁺. Anal. calc.for C₁₈H₁₅N₂FSO₃ 0.25H₂O: C, 59.57; H, 4.30; N, 7.71. Found: C, 59.28;H, 4.39; N, 8.39

EXAMPLE 642-(2,2,2-Trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-6-methyl-3(2H)-pyridazinone

The product of Example 63 (100 mg, 0.28 mmol) was dissolved in anhydrousDMF (3 mL) and treated with 1,1,1-trifluoro-2-iodoethane (27.5 mL, 280mmol) in presence of anhydrous sodium carbonate (130 mg, 1.2 mmol) at50-60° C. for 2 hours. The reaction mixture was partitioned betweenwater and ethyl acetate to provide the desired compound as an amorphoussolid (60 mg, 48%). ¹H NMR (300 MHz, CDCl₃) δ2.10 (s, 3H), 3.10 (s, 3H),4.85 (q, J=9 Hz, 2H), 6.90 (m, 2H), 7.10 (dd, J=6 Hz, J=9 Hz, 2H), 7.25(m, 2H), 7.95 (d, J=9 Hz, 2H), MS (DCI/NH₃) 458 (M+N₄)⁺ Anal. calc. forC₂₀H₁₆N₂F₄SO₃: C, 54.54; H, 3.66; N, 6.36. Found: C, 54.41; H, 3.56; N,6.35.

EXAMPLE 652-Benzyl-4-(3,4-dichlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared by coupling 3,4-dichlorophenylboronicacid with 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone (J. Het. Chem.,(1996) 33, 1579-1582) according to the method of Example 6. This productwas converted to the 5-hydroxy-derivative according to the method ofExample 7. The 5-hydroxy compound was converted to the5-trifluoromethylsulfonyloxy-derivative according to the method ofExample 8. Coupling of 4-(methylthio)phenylboronic acid to the triflateaccording to the method of Example 9 provided the5-[4-(methylthio)phenyl]-intermediate which was oxidized according tothe method of Example 10 to provide the final product (yield: 780 mg,84%). mp 161-163° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.22 (s, 3H), 5.35 (s,2H), 7.08 (dd, J=9 Hz, 3 Hz, 1H), 7.32-7.44 (m, 5H), 7.47 (dd, J=9 Hz, 3Hz, 3H), 7.48 (d, J=3 Hz, 1H), 7.90 (d, J=9 Hz, 2H), 8.13 (s, 1H). MS(DCI/NH3) m/z 485 (M+H)⁺. Anal. calc. for C₂₄H₁₈Cl₂N₂O₃S: C, 59.38; H,3.73; N, 5.77. Found: C, 59.28; H, 3.92; N, 5.42.

EXAMPLE 662-(2,2,2-Trifluoroethyl)-4-(4-n-propylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared by coupling 4-(n-propyl)phenylboronicacid with 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone (J. Het. Chem.,1996, 33, 1579-1582) according to the method of Example 6. This productwas converted to the 5-hydroxy derivative according to the method ofExample 7. This product was converted to the5-trifluoromethylsulfonyloxy-derivative according to the method ofExample 8. Coupling of 4-(methylthio)phenylboronic acid to the triflateaccording to the method of Example 9 provided the5-[4-(methylthio)phenyl]-intermediate which was oxidized according tothe method of Example 10 to provide the final product (yield: 220 mg,70%). mp 64-66° C. ¹H NMR (300 MHz, CDCl₃) δ 0.91 (t, J=7.5 Hz, 3H), 1.6(h, J=7.5 Hz, 2H), 2.55 (q, J=7.5 Hz, 2H), 3.05 (s, 3H), 4.88 (q, J=9Hz, 2H), 7.08 (s, 4H), 7.35 (d, J=9 Hz, 2H), 7.86 (d, J=9 Hz, 2H), 7.87(s, 1H). MS (DCI/NH₃) m/z 451 (M+H)⁺. Anal. calc. for C₂₂H₂₁F₃N₂O₃S: C,58.65; H, 4.69; N, 6.21. Found: C, 58.71; H, 4.72; N, 6.20.

EXAMPLE 672-(2,2,2-Trifluoroethyl)-4-(4-chloro-3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared by first coupling3-fluoro-4-chlorophenylboronic acid with2-benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone according to the methodof Example 6. The product was converted to the 5-hydroxy compoundaccording to the method of Example 7. This 5-hydroxy compound wasconverted to the 5-trifluoromethylsulfonyloxy-derivative according tothe method of Example 8. Coupling of 4-(methylthio)phenylboronic acid tothe triflate according to the method of Example 9 provided the5-[4-(methylthio)phenyl]-intermediate which was oxidized according tothe method of Example 10 to provide the final product (yield: 170 mg,84%). mp 174-175° C. ¹H NMR (300 MHz, CDCl₃) δ 3.09 (s, 3H), 4.89 (q,J=9 Hz, 2H), 6.87 (din, J=9 Hz, 1H), 7.09 (dd, J=9 Hz, 3 Hz, 1H), 7.30(t, J=9 Hz, 1H), 7.39 (d, J=9 Hz, 2H), 7.91 (s, 1H), 7.95 (d, J=9 Hz,2H). MS (DCI/NH₃) m/z 461 (M+H)⁺. Anal. calc. for C₁₉H₁₃ClF₄N₂O₃S: C,49.52; H, 2.84; N, 6.07. Found: C, 49.66; H, 2.70; N, 5.96.

EXAMPLE 682-(2,2,2-Trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

A solution of2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone(680 mg, 1.53 mmol) in trifluoroacetic anhydride (30 mL) was stirred atroom temperature for 1 hour. The excess solvent was evaporated in vacuoand the residue was treated with a deoxygenated 1N solution ofmethanol-NaOH (50 mL, 4:1) at 0° C. The solution was stirred at roomtemperature for 2 hours and quenched with dilute HCl solution untilacidic. The white suspension formed was concentrated in vacuo toevaporate the methanol. THF was added to the resulting suspension untila clear solution was obtained. Chlorine gas was slowly bubbled into thesolution, maintained at 0° C. After 10 minutes, nitrogen gas was bubbledinto the solution for a few minutes to displace residual chlorine.Ammonium hydroxide solution (30%, 5 to 10 mL), at 0° C., was slowlyadded to the solution (to consume all starting sulfonyl chloride) andstirred at room temperature for 5 minutes The solution was partitionedbetween water and ethyl acetate. The organic layer was washed first withwater, then brine, and dried over MgSO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by chromatography onsilica gel (40:60 ethyl acetate/hexanes) to provide the title compound(yield: 500 mg, 75%). mp 193-195° C. ¹H NMR (300 MHz, CDCl₃) δ 4.82 (s,2H), 4.88 (q, J=9 Hz, 2H), 6.98 (t, J=9 Hz, 2H), 7.19 (dd, J=9 Hz, 6 Hz,2H), 7.30 (d, J=9 Hz, 2H), 7.88 (d, J=9 Hz, 2H), 7.90 (s, 1H). MS(DCI/NH₃) m/z 428 (M+H)⁺. Anal. calc. for C₁₈H₁₃F₄N₃O₃S: C, 50.58; H,3.06; N, 9.83. Found: C, 51.04; H, 3.26; N, 9.63.

EXAMPLE 692-(2,2,2-Trifluoroethyl)-4-(4-chlorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound from Example 77 was converted to the sulfonamideproduct according to the method of Example 68 (yield: 540 mg, 70%). mp154-156° C. ¹H NMR (300 MHz, CDCl₃) δ 4.86 (s, 2H), 4.87 (q, J=9 Hz,2H), 7.14 (d, J=9 Hz, 2H), 7.29 (d, J=9 Hz, 2H), 7.31 (d, J=9 Hz, 2H),7.89 (d, J=9 Hz, 2H), 8.00 (s, 1H). MS (DCI/NH₃) m/z 444 (M+H)⁺. Anal.calc. for C₁₈H₁₃ClF₃N₃O₃S: C, 48.71; H, 2.95; N, 9.46. Found: C, 49.05;H, 3.01; N, 9.15.

EXAMPLE 702-(2,2,2-Trifluoroethyl)-4-(2-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The methyl sulfide intermediate prepared in Example 83C was oxidizedwith one equivalent of meta-chloroperoxybenzoic acid to provide themethylsulfoxide which was converted to the sulfonamide final productaccording to the method of Example 68 (yield: 396 mg, 60%). mp 158-160°C. ¹H NMR (300 MHz, CDCl₃) δ 1.21 (d, J=6 Hz, 6H), 4.83 (q, J=7.5 Hz,2H), 4.86 (s, 2H), 5.46 (p, J=6 Hz, 1H), 7.72 (d, J=9 Hz, 2H), 7.82 (s,1H), 8.03 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 392 (M+H)⁺. Anal. calc. forC₁₅H₁₆F₃N₃O₄S: C, 46.03; H, 4.12; N, 10.73. Found: C, 46.08; H, 4.22; N,10.52.

EXAMPLE 712-(2,2,2-Trifluoroethyl)-4-(4-fluorophenoxy)-5-[4-(aminosulfonyl)-phenyl]-3(2H)-pyridazinone

The methyl sulfide intermediate of Example 76 was oxidized with oneequivalent of meta-chloroperoxybenzoic acid to provide themethylsulfoxide which was converted to the sulfonamide final productaccording to the method of Example 68 (yield: 180 mg, 37%). mp 150-152°C. ¹H NMR (300 MHz, CDCl₃) δ 4.71 (q, J=7.5 Hz, 2H), 4.72 (s, 2H), 6.88(dd, J=9 Hz, 4.5 Hz, 2H), 7.0 (t, J=9 Hz, 2H), 7.73 (d, J=9 Hz, 2H),7.98 (s, 1H), 8.05 (d, J=9 Hz, 2H). MS (DCI/NH₃) M/Z 444 (M+H)⁺. Anal.calc. for C₁₈H₁₃F₄N₃O₄S: C, 48.76; H, 2.95; N, 9.47. Found: C, 48.49; H,2.8; N, 8.95.

EXAMPLE 722,4-Bis-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 72A 2-Fluorothioanisole

A deoxygenated solution of 2-fluorothiophenol (10 g, 78 mmol) inanhydrous DMF (10 mL) was treated with iodomethane (4.9 mL, 78 mmol) andpotassium carbonate (10.8 g, 78 mmol). The reaction mixture was stirredat room temperature for 1 hour. A thin layer chromotography (100%hexanes) sample indicated that the reaction had not gone to completion,so an additional equivalent of base and iodomethane were added and thereaction mixture was stirred overnight at room temperature. The reactionwas acidified with 10% aqueous citric acid and extracted with hexanes(2×125 mL). The combined organic extracts were washed with brine, driedover MgSO₄, and filtered. The filtrate was concentrated under reducedpressure to provide the desired compound as a pale yellow oil (yield:6.68 g; 60%).

EXAMPLE 72B 2-Fluorothioanisole

An alternative method for preparing 2-fluorothioanisole begins with asolution of 1,2-difluorobenzene (0.79 mL, 8 mmol) in anhydrous DMF (50mL) was treated with sodium thiomethoxide (0.59 g, 8 mmol). The reactionmixture was stirred at room temperature for 6 hours, and partitionedbetween hexanes and water. The organic layer was washed with brine,dried over MgSO₄, and filtered. The filtrate was concentrated underreduced pressure to provide the desired compound (1.1 g, 100%) slightlycontaminated with 1,2-bis(methylthio)benzene, a lower Rf material, whichwas removed by chromatography with 100% hexanes (0.9 g, 80%). ¹H NMR(300 MHz, CDCl₃) δ 2.46 (s, 3H), 6.98-7.19 (m, 3H) 2.26 (dt, J=9 Hz, 3Hz, 1H).

EXAMPLE 72C 4-Bromo-2-fluorothioanisole

A solution of 2-fluorothioanisole (1.42 g, 10 mmol) and iron powder(0.03 g, 0.5 mmol) in dichloromethane (20 mL) was chilled to ° C. andtreated dropwise with Bromine (0.5 mL, 10 mmol). Upon completion of theBromine treatment, the reaction was sampled for TLC (100% hexanes). Anew, higher Rf material was present but the reaction had not gone tocompletion so another equivalent of bromine was added along with acatalytic amount of aluminum chloride. The reaction mixture was stirredovernight at room temperature. Aqueous sodium sulfite was added to thereaction mixture and the organic layer was isolated, dried over MgSO₄,and filtered. The filtrate was filtered through a pad of silica gel toremove color then concentrated under reduced pressure to provide theproduct as a clear, colorless oil (yield: 1.3 g; 60%). ¹H NMR (300 MHz,DMSO-d₆)δ 2.48 (s, 3H), 7.31 (t, J=9 Hz, 1H), 7.43 (dd, J=9 Hz, 3 Hz,1H) 7.54 (dd, J=9 Hz, 3 Hz, 1H).

EXAMPLE 72D 3-Fluoro-4-(methylthio)benzeneboronic acid

A solution of 4-bromo-2-fluorothioanisole (0.5 g, 22.6 mmol) in dry THF(20 mL) was chilled to −78° C. under a nitrogen atmosphere. The reactionmixture was treated with 1.6 M n-butyllithium in hexanes (1.7 mL, 27.1mmol), and the mixture was warmed to −40° C. where it was maintained for0.5 hours. The reaction mixture was then chilled to −78° C. and threeequivalents of triisopropyl borate (1.56 mL, 67.8 mmol) were added. Thereaction mixture was allowed to warm to room temperature and stirred for1.5 hours. At this point, 10% aqueous KOH (200 mL, 360 mmol) was addedand the mixture was stirred overnight at room temperature. The reactionmixture was then poured into an ice/concentrated HCl mixture withstirring to yield a white precipitate. This solid was dried in a vacuumoven (65° C., 29 in Hg) overnight to provide the title compound (yield:0.22 g; 52.4%). ¹H NMR (300 MHz, DMSO-d₆) δ 2.48 (s, 3H), 7.31 (t, J=9Hz, 1H), 7.49 (dd, J=12 Hz, 1.5 Hz, 1H) 7.54 (dd, J=9 Hz, 1.5 Hz, 1H).

EXAMPLE 72E2,4-Bis-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33,1579-1582) was converted to the 5-hydroxy-analog according to the methodof Example 7 and then to the 5-trifluoromethylsulfonyloxy-analogfollowing the method of Example 8. Subsequent coupling to3-fluoro-4-(methylthio)phenylboronic acid, according to the method ofExample 9, provided2-benzyl-4-chloro-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone.This intermediate was coupled in the 4-position with4-fluorophenylboronic acid following the method of Example 6. Thisproduct was N-debenzylated according to the method of Example 11 andN-arylated with 4-fluoroiodobenzene according to the method of Example62. The resulting sulfide was oxidized with one equivalent ofmeta-chloroperoxybenzoic acid to provide the methylsulfoxide which wasconverted to the sulfonamide final product according to the method ofExample 68 (yield: 500 mg, 75%). mp 222-224° C. ¹H NMR (300 MHz, CDCl₃)δ 5.06 (s, 2H), 7.01 (t, J=9 Hz, 2H), 7.06 (d, J=9 Hz, 2H), 7.10 (d, J=9Hz, 2H), 7.18 (t, J=9 Hz, 2H), 7.69 (dd, J=9 Hz, 3 Hz, 2H), 7.88 (t, J=9Hz, 1H), 7.95 (s, 1H). MS (DCI/NH₃) m/z 458 (M+H)⁺. Anal. calc. forC₂₂H₁₄F₃N₃O₃S: C, 57.76; H, 3.08; N, 9.18. Found: C, 57.5; H, 3.15; N,8.8.

EXAMPLE 732-(2,2,2-Trifluoroethyl)-4-(4-chloro-3-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The methyl sulfide intermediate prepared in Example 67 was oxidized withone equivalent of meta-chloroperoxybenzoic acid, according to the methodof Example 68 to provide the methyl sulfoxide. The methyl sulfoxide wasconverted to the sulfonamide product according to the method of Example68 (yield: 1.5 g, 63%). mp 180-183° C. ¹H NMR (300 MHz, DMSO-d₆) δ 5.09(q, J=9 Hz, 2H), 7.01 (dd, J=9 Hz, 3 Hz, 1H), 7.15 (dd, J=9 Hz, 3 Hz,1H), 7.39 (dd, J=9 Hz, 3 Hz, 1H), 7.47 (dd, J=9 Hz, 3 Hz, 1H), 7.55 (t,J=9 Hz, 1H), 7.71 (t, J=9 Hz, 1H), 7.78 (s, 2H), 8.37 (s, 1H). MS(DCI/NH₃) m/z 480 (M+H)⁺. Anal. calc. for C₁₈H₁₁ClF₅N₃O₃S: C, 45.05; H,2.31; N, 8.75. Found: C, 46.19; H, 3.02; N, 7.43.

EXAMPLE 742-Benzyl-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33,1579-1582) was converted to the 5-hydroxy-analog according to the methodof Example 7 and then to the 5-trifluoromethylsulfonyloxy-analogfollowing the method of Example 8. Subsequent coupling to4-(methylthio)phenylboronic acid according to the method of Example 9provided 2-benzyl-4-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone.This 4-chloro-intermediate thus prepared was treated with 2-propanol (20mL, 261 mmol) and potassium t-butoxide (110 mg, 0.98 mmol) at reflux for45 minutes furnished2-benzyl-4-(2-propoxy)-5-[4-(methylthio)pentyl]-3(2H)-pyridazinone Thismethyl sulfide was oxidized according to the method of Example 10 toprovide the title compound (yield: 180 mg, 80%). mp 109-111° C. ¹H NMR(300 MHz, CDCl₃) δ 1.18 (d, J=6 Hz, 6H), 3.12 (s, 3H), 5.36 (s, 2H),5.49 (h, J=6 Hz, 1H), 7.35 (m, 3H), +7.47 (dd, J=9 Hz, 3 Hz, 2H), 7.74(d, J=9 Hz, 2H), 7.79 (s, 1H), 8.03 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z399 (+H)⁺. Anal. calc. for C₂₁H₂₂N₂O₄S: C, 63.29; H, 5.56; N, 7.03.Found: C, 63.17; H, 5.57; N, 6.95.

EXAMPLE 752-Benzyl-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 74substituting 4-fluorophenol in place of 2-propanol (yield: 180 mg, 99%).mp 188-190° C. ¹H NMR (300 MHz, CDCl₃) δ 3.12 (s, 3H), 5.26 (s, 2H),6.86 (dd, J=9 Hz, 6 Hz, 2H), 6.99 (t, J=9 Hz, 2H), 7.34 (m, 3H), 7.46(dd, J=9 Hz, 3 Hz, 2H), 7.72 (d, J=9 Hz, 2H), 7.92 (s, 1H), 8.02 (d, J=9Hz, 2H). MS (DCI/NH₃) m/z 451 (+H)⁺. Anal. calc. for C₂₄H₁₉FN₂O₄S: C,63.98; H, 4.25; N, 6.21. Found: C, 63.74; H, 4.2; N, 6.12.

EXAMPLE 762-(2,2,2-Trifluoroethyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 75substituting2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 180 mg, 63%). mp 161-164° C. ¹H NMR (300 MHz, CDCl₃) δ 3.09 (s,3H), 4.81 (q, J=9 Hz, 2H), 6.88 (dd, J=9 Hz, 4.5 Hz, 2H), 7.0 (t, J=9Hz, 2H), 7.78 (d, J=9 Hz, 2H), 7.79 (s, 1H), 8.06 (d, J=9 Hz, 2H). MS(DCI/NH₃) m/z 443 (M+H)⁺. Anal. calc. for C₁₉H₁₄F₄N₂O₄S: C, 51.58; H,3.18; N, 6.33. Found: C, 51.8; H, 3.3; N, 6.22.

EXAMPLE 772-(2,2,2-Trifluoroethyl)-4-(4-chlorophenyl)-5-[4-(methylsulfinyl)-phenyl]-3(2H)-pyridazinone

2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33,1579-1582) was converted to the 5-hydroxy-analog according to the methodof Example 7 and then to the 5-trifluoromethylsulfonyloxy-analogaccording to the method of Example 8. Subsequent coupling to4-(methylthio)phenylboronic acid, according to the method of Example 9,provided 2-benzyl-4-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone.This intermediate was coupled with 4-chlorophenylboronic acid accordingto the method of Example 6. This product was N-debenzylated according tothe method of Example 11 and N-alkylated with2-iodo-1,1,1-trifluoroethane according to the method of Example 20. Theresulting sulfide was oxidized to the corresponding sulfoxide with oneequivalent of meta-chloroperoxybenzoic acid, according to the method ofExample 5 to provide the title compound (yield: 130 mg, 70%). mp154-155° C. ¹H NMR (300 MHz, CDCl₃) δ 2.74 (s, 3H), 4.88 (q, J=9 Hz,2H), 7.14 (d, J=9 Hz, 2H), 7.26 (d, J=9 Hz, 2H), 7.31 (d, J=9 Hz, 2H),7.61 (d, J=9 Hz, 2H), 7.82 (s, 1H). MS (DCI/NH₃) m/z 427 (M+H)⁺. Anal.calc. for C₁₉H₁₄ClF₃N₂O₂S: C, 53.46; H, 3.3; N, 6.56. Found: C, 53.58;H, 3.34; N, 6.42.

EXAMPLE 782-Benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared by oxidizing2-benzyl-4-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, (preparedas an intermediate in Example 77) according to the method of Example 10(yield: 180 mg, 83%). mp 166-167° C. ¹H NMR (300 MHz, CDCl₃) δ 3.12 (s,3H), 5.41 (s, 2H), 7.37 (m, 3H), 7.53 (dd, J=9 Hz, 3 Hz, 2H), 7.68 (d,J=9 Hz, 2H), 7.74 (s, 1H), 8.08 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 375(M+H)⁺. Anal. calc. for C₁₈H₁₅ClN₂O₃S: C, 57.67; H, 4.03; N, 7.47.Found: C, 57.43; H, 4.06; N, 7.35.

EXAMPLE 792-(2,2,2-Trifluoroethyl)-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-Benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33,1579-1582) was converted to the 5-hydroxy-analog according to the methodof Example 7 and then to the 5-(trifluoromethyl)sulfonyloxy-analogaccording to the method of Example 8. Subsequent coupling to4-(methylthio)phenylboronic acid, according to the method of Example 9,provided 2-benzyl-4-bromo-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone.This intermediate was coupled with 4-methylphenylboronic acid accordingto the method of Example 6. This product was N-debenzylated according tothe method of Example 11 and N-alkylated with2-iodo-1,1,1-trifluoroethane according to the method of Example 20. Theresulting sulfide was oxidized to the title compound according to themethod of Example 10 (yield: 210 mg, 98%). mp 154-156° C. ¹H NMR (300MHz, CDCl₃) δ 2.33 (s, 3H), 3.07 (s, 3H), 4.89 (q, J=9 Hz, 2H), 7.08 (s,4H), 7.37 (d, J=9 Hz, 2H), 7.88 (s, 1H), 7.89 (d, J=9 Hz, 2H). MS(DCI/NH₃) m/z 423 (M+H)⁺. Anal. calc. for C₂₀H₁₇F₃N₂O₃S: C, 56.86; H,4.05; N, 6.63. Found: C, 56.59; H, 4.11; N, 6.53.

EXAMPLE 802-(2,2,2H-Trifluoroethyl)-4-(4-chloro-3-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33,1579-1582) was converted to the 5-hydroxy-analog according to the methodof Example 7 and then to the 5-(trifluoromethyl)sulfonyloxy-analogaccording to the method of Example 8. Subsequent coupling to4-(methylthio)phenylboronic acid, according to the method of Example 9,provided 2-benzyl-4-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone.This intermediate was coupled with 4-chloro-3-fluorophenylboronic acidaccording to the method of Example 6. This product was N-debenzylatedaccording to the method of Example 11 and N-alkylated with2-iodo-1,1,1-trifluoroethane according to the method of Example 20. Theresulting sulfide was oxidized to the corresponding sulfoxide with oneequivalent of meta-chloroperoxybenzoic acid to provide themethylsulfoxide which was converted to the sulfonamide final productaccording to the method of Example 68 (yield: 500 mg, 75%). mp 214-215°C. ¹H NMR (300 MHz, CDCl₃) δ 4.82 (s, 2H), 4.88 (q, J=9 Hz, 2H), 6.88(m, 1H), 7.09 (dd, J=9 Hz, 3 Hz, 1H), 7.31 (d, J=9 Hz, 1H), 7.32 (d, J=9Hz, 2H), 7.90 (s, 1H), 7.92 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 462(M+H)⁺. Anal. calc. for C₁₈H₁₂F₄ClN₃O₃S: C, 46.81; H, 2.61; N, 9.09.Found: C, 46.79; H, 2.59; N, 8.86.

EXAMPLE 812-(2,2,2-Trifluoroethyl)-4-(3,4-dichlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product described in Example 65 was N-debenzylated according to themethod of Example 11. The intermediate was N-alkylated according to themethod of Example 20, substituting 2-iodo-1,1,1-trifluoroethane in placeof 4-fluorobenzyl bromide to provide the title compound (yield: 165 mg,55%). mp 197-198° C. ¹H NMR (300 MHz, CDCl₃) δ 3.09 (s, 3H), 4.88 (q,J=9 Hz, 2H), 6.98 (dd, J=9 Hz, 3 Hz, 1H), 7.37 (d, J=9 Hz, 4H), 7.91 (s,1H), 7.95 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 477 (M+H)⁺. Anal. calc. forC₁₉H₁₃F₃Cl₂N₂O₃S: C, 47.81; H, 2.74; N, 5.86. Found: C, 47.94; H, 2.87;N, 5.83.

EXAMPLE 822-Benzyl-4-(2-propylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-Benzyl-4,5-dibromo-3(2H)-pyridazinone (2 g, 6 mmol) was reacted with2-aminopropane (2 mL, 23.5 mmol) and potassium t-butoxide (910 mg, 6.6mmol) in toluene (40 mL) at reflux for 18 hours to provide the4-(2-propylamino) derivative after column chromatography (silica gel,92:8 hexanes/ethyl acetate). The intermediate was coupled in the5-position with 4-(methylthio)phenylboronic acid according to the methodof Example 6. The methyl sulfide was oxidized, according to the methodof Example 10, to provide the title compound (yield: 120 mg, 48%). mp146-147° C. ¹H NMR (300 MHz, CDCl₃) δ 0.92 (d, J=6 Hz, 6H), 3.11 (m,1H), 3.13 (s, 3H), 5.34 (s, 2H), 5.59 (m, 1H), 7.33 (m, 3H), 7.42 (s,1H), 7.48 (dd, J=9 Hz, 3 Hz, 2H), 7.56 (d, J=9 Hz, 2H), 8.00 (d, J=9 Hz,2H). MS (DCI/NH₃) m/z 399 (M+H)⁺. Anal. calc. for C₂₁H₂₃N₃O₃S: C, 63.45;H, 5.83; N, 10.57. Found: C, 63.31; H, 5.87; N, 10.44.

EXAMPLE 832-(2,2,2-Trifluoroethyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 83A 2-(2,2,2-Trifluoroethyl)-4,5-dibromo-3(2H)-pyridazinone

A solution of mucobromic acid (10 g, 38.8 mmol) and trifluoroethylhydrazine

(70% in water, 4.88 mL, 38.8 mmol) in 100 mL of methanol was preparedand heated at reflux for 3 hours. The reaction mixture was concentratedin vacuo and partitioned between ethyl acetate and water. The ethylacetate layer was dried over MgSO₄, filtered, passed through a silicagel pad, and concentrated in vacuo. The product was obtained asyellowish solid (yield: 8.8 g, 68%). ¹H NMR (300 MHz, CDCl₃) δ 4.78 (q,J=9 Hz, 2H), 7.87 (s, 1H). MS (DCI/NH₃) m/z 337 (M+H)⁺.

EXAMPLE 83B2-(2,2,2-Trifluoroethyl)-4-(2-propoxy)-5-bromo-3(2H)-pyridazinone

A solution of 2-(2,2,2-trifluoroethyl)-4,5-dibromo-3(2H)-pyridazinone (2g, 6 mmol), isopropyl alcohol (3 mL) and sodium hydride (60% dispersedin oil, 290 mg, 7.2 mmol) in toluene (40 mL) was heated at reflux for 5hours. The reaction mixture was partitioned between ethyl acetate andwater. The ethyl acetate layer was filtered, and concentrated in vacuo.The residue was purified by chromatography (95:5 hexanes/ethyl acetate)to provide the product as a greenish oil (yield: 1.22 g, 65%). ¹H NMR(300 MHz, CDCl₃) δ 1.46 (d, J=7.5 Hz, 6H), 5.48 (h, J=6 Hz, 1H), 7.87(s, 1H). MS (DCI/NH₃) m/z 316 (M+H)⁺.

EXAMPLE 83C2-(2,2,2-Trifluoroethyl)-4-(2-propoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

A solution of2-(2,2,2-trifluoroethyl)-4-(2-propoxy)-5-bromo-3(2H)-pyridazinone (1.2g, 3.8 mmol), 4-(methylthio)phenylboronic acid (704 mg, 4.19 mmol),tetrakis(triphenylphosphine)palladium(0) (220 mg, 5% mmol) and cesiumcarbonate (2.72 g, 8.3 mmol) in 20 mL of ethylene glycol dimethyl etherwas heated to reflux for 5 hours. The mixture was partitioned betweenethyl acetate and water. The ethyl acetate layer was washed with water,brine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by chromatography on silica gel (94:6 hexanes/ethyl acetate).The product was obtained as a greenish solid (yield: 1.1 g, 81%). ¹H NMR(300 MHz, CDCl₃) δ 1.19 (d, J=7.5 Hz, 6H); 2.55 (s, 3H), 4.83 (q, J=9Hz, 2H), 5.28 (h, J=6 Hz, 1H), 7.32 (d, J=9 Hz, 2H), 7.52 (d, J=9 Hz,2H), 7.85 (s, 1H). MS (DCI) m/z 359 (M+H)⁺.

EXAMPLE 83D2-(2,2,2-Trifluoroethyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 10,substituting2-(2,2,2-trifluoroethyl)-4-(2-propoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonein place of4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield:220 mg, 100%). mp 152-153° C. ¹H NMR (300 MHz, CDCl₃) δ 1.2 (d, J=6 Hz,6H), 3.13 (s, 3H), 4.84 (q, J=9 Hz, 2H), 5.49 (p, J=6 Hz, 1H), 7.78 (d,J=9 Hz, 2H), 7.82 (s, 1H), 8.05 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 391(M+H)⁺. Anal. calc. for C₁₆H₁₇F₃N₂O₄S: C, 49.22; H, 4.38; N, 7.17.Found: C, 49.34; H, 4.25; N, 7.01.

EXAMPLE 842-(2,2,2-Trifluoroethyl)-4-cyclohexyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 83,substituting cyclohexanol in place of 2-propanol (yield: 250 mg, 52%).mp 129-130° C. ¹H NMR (300 MHz, CDCl₃) δ 1.1-1.6 (m, 8H), 1.84 (m, 2H),3.12 (s, 3H), 4.83 (q, J=9 Hz, 2H), 5.21 (h, J=4.5 Hz, 1H), 7.77 (s,1H), 7.80 (d, J=9 Hz, 2H), 8.06 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 431(M+H)⁺. Anal. calc. for C₁₉H₂₁F₃N₂O₄S: C, 53.01; H, 4.91; N, 6.50.Found: C, 52.96; H, 4.84; N, 6.45.

EXAMPLE 852-(2,2,2-Trifluoroethyl)-4-cyclopentyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 83,substituting cyclopentanol in place of 2-propanol (yield: 250 mg, 52%).mp 148-150° C. ¹H NMR (300 MHz, CDCl₃) δ 1.35-1.55 (m, 4H), 1.68-1.75(m, 4H), 3.12 (s, 3H), 4.83 (q, J=9 Hz, 2H), 5.89 (h, J=4.5 Hz, 1H),7.75 (d, J=9 Hz, 2H), 7.83 (s, 1H), 8.04 (d, J=9 Hz, 2H). MS (DCI/NH₃)m/z 417 (M+H)⁺. Anal. calc. for C₁₈H₁₉F₃N₂O₄S: C, 51.91; H, 4.59; N,6.72. Found: C, 52.04; H, 4.50; N, 6.65.

EXAMPLE 862-(2,2,2-Trifluoroethyl)-4-(2-propylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 86A2-(2,2,2-Trifluoroethyl)-4-(2-propylamino)-5-bromo-3(2H)-pyridazinone

The title compound was prepared according method of the Example 83B,substituting 2-propylamine in place of 2-propanol (yield: 70%). MS(DCI/NH₃) m/z 315 (M+H)⁺.

EXAMPLE 86B2-(2,2,2-Trifluoroethyl)-4-(2-propylamino)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

The title compound was prepared according method of the Example 83C,substituting2-(2,2,2-trifluoroethyl)-4-(2-propylamino)-5-bromo-3(2H)-pyridazinone inplace of2-(2,2,2-trifluoroethyl)-4-isopropoxy-5-bromo-3(2H)-pyridazinone (yield:80%). MS (DCI/NH₃) M/Z 358 (M+H)⁺.

EXAMPLE 86C2-(2,2,2-Trifluoroethyl)-4-(2-propylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone

The title compound was prepared according to the method of Example 10,substituting2-(2,2,2-Trifluoroethyl)-4-(2-propylamino)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonein place of4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield:180 mg, 83%). mp 173-174° C. ¹H NMR (300 MHz, CDCl₃) δ 0.95 (d, J=6 Hz,6H), 3.13 (s, 3H), 4.81 (q, J=9 Hz, 2H), 5.97 (s, 1H), 7.45 (s, 1H),7.59 (d, J=9 Hz, 2H), 8.03 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 340 (M+H)⁺.Anal. calc. for C₁₆H₁₈F₃N₃O₄S: C, 49.35; H, 4.65; N, 10.79. Found: C,49.29; H, 4.52; N, 10.65.

EXAMPLE 872-Benzyl-4-(4-morpholino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-Benzyl-4,5-dichloro-3(2H)-pyridazinone, prepared following theprocedure in Example 2, was reacted with morpholine following theprocedure of Example 86 to provide the 4-morpholino-derivative. Themorpholino intermediate was coupled at the 5-position with4-(methylthio)phenylboronic acid according to the method of Example 6.The resulting methyl sulfide was oxidized to the title compoundaccording to the method of Example 10 (yield: 150 mg, 69%). mp 158-160°C. ¹H NMR (300 MHz, CDCl₃) δ 3.06 (t, J=4.5 Hz, 3H), 3.12 (s, 3H), 3.69(t, J=4.5 Hz, 3H), 5.33 (s, 2H), 7.35 (m, 3H), 7.5 (m, 4H), 7.58 (s,1H), 8.05 (d, J=9 Hz, 2H). MS (DCI/N₃) m/z 426 (M+H)⁺. Anal. calc. forC₂₂H₂₃N₃O₄S: C, 62.10; H, 5.44; N, 9.87. Found: C, 61.74; H, 5.47; N,9.59.

EXAMPLE 882-(2,3,3-Trifluoro-2-propen-1-yl)]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 88A 1-Methylsulfonyloxy-2,3,3-trifluoro-2-propene

2,3,3-Trifluoro-2-propen-1-ol was prepared as reported in (J. Org.Chem., (1989) 54, 5640-5642). The mesylate was obtained by reacting2,3,3-trifluoro-2-propen-1-ol with mesyl chloride in diethyl ether.Standard workup provided the product, which was used withoutpurification.

EXAMPLE 88B2-(2,3,3-Trifluoro-2-propen-1-yl)-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

4-(4-Fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone isprepared starting with the 2-benzyl-pyridazinone from Example 9 anddebenzylating the compound according to the procedure of Example 11.

A mixture of4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (250 mg,0.8 mmol), Cs₂CO₃ (650 mg, 2 mmol), and3-methylsulfonyloxy-1,1,2-trifluoropropene (mesylate, 250 mg, 1.19 mmol)in ethyl acetate (30 mL) was stirred at 55° C. for 1.5 hours. Themixture was partitioned between ethyl acetate and water. The organiclayer was washed with brine, dried with MgSO₄ and filtered. The filtratewas concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluted with 15% ethyl acetate/hexanes, toprovide the methyl sulfide,2-(2,3,3-trifluoro-2-propen-1-yl)-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneas a greenish oil (yield: 175 mg, 53%).

EXAMPLE 88C2-(2,3,3-Trifluoro-2-propen-1-yl)]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The methyl sulfide, prepared above, was oxidized to the title compoundaccording to the method of Example 10 (yield: 125 mg, 68%). mp 154-156°C. ¹H NMR (300 MHz, CDCl₃) δ 3.07 (s, 3H), 5.1 (ddd, J=21 Hz, 3 Hz, 1.5Hz, 2H), 6.98 (t, J=9 Hz, 2H), 7.19 (dd, J=9 Hz, 6 Hz, 2H), 7.35 (d, J=9Hz, 2H), 7.89 (s, 1H), 7.9 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 439 (M+H)⁺.Anal. calc. for C₂₀H₁₄F₄N₂O₃S: C, 54.79; H, 3.21; N, 6.38. Found: C,54.52; H, 3.15; N, 6.21.

EXAMPLE 892,4-Bis(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 68substituting2,4-bis(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinonein place of2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone(yield: 118 mg, 43%). mp 213-216° C. ¹H NMR (300 MHz, DMSO-d₆) δ 7.15(t, 2H), 7.27 (m, 2H), 7.4 (m, 6H), 7.7 (dd, 2H), 7.76 (d, J=9 Hz; 2H),8.2 (s, 1H). MS (DCI/NH₃) m/z 440 (M+H)⁺, 439.44 (M+NH₄)⁺. Anal. calc.for C₂₁H₁₅FN₂O₃S₂: C, 60.13; H, 3.44; N, 9.56. Found: C, 59.94; H, 3.37;N, 9.46.

EXAMPLE 902-(2,2,2-Trifluoroethyl)-4-cyclopropylmethoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 90A2-(2,2,2-Trifluoroethyl)-4-methoxy-5-bromo-3(2H)-pyridazinone

The title compound was prepared according method of the Example 83B,substituting methanol in place of isopropanol (yield: 78%). ¹H NMR (300MHz, CDCl₃) δ 4.3 (s, 3H), 4.76 (q, J=9 Hz, 2H), 7.85 (s, 1H). MS(DCI/NH₃) m/z 288 (M+H)⁺.

EXAMPLE 90B2-(2,2,2-Trifluoroethyl)₄-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

The title compound was prepared according method of the Example 83C,substituting2-(2,2,2-trifluoroethyl)-4-methoxy-5-bromo-3(2H)-pyridazinone in placeof 2-(2,2,2-trifluoroethyl)-4-(2-propoxy)-5-bromo-3(2H)-pyridazinone(yield: 80%). ¹H NMR (300 MHz, CDCl₃) δ 2.54 (s, 3H), 4.11 (s, 3H), 4.82(q, J=9 Hz, 2H), 7.33 (d, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 2H), 7.84 (s,1H). MS (DCI/NH₃) m/z 331 (M+H)⁺.

EXAMPLE 9° C.2-(2,2,2-Trifluoroethyl)-4-hydroxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

A solution of2-(2,2,2-Trifluoroethyl)₄-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(2 g, 6.1 mmol) and hydrobromic acid (40% in water, 20 mL) in aceticacid (40 mL) was heated at reflux for 3 hours. The reaction mixture wascooled to room temperature and water (50 mL) was added. The crystalsformed were filtered, washed with water and 5% ethyl acetate in hexanes,and dried to constant weight. The product was obtained as a white solid(yield: 1.75 g, 91%). ¹H NMR (300 MHz, CDCl₃) δ 2.54 (s, 3H), 4.82 (q,J=9 Hz, 2H), 7.47 (d, J=9 Hz, 2H), 7.65 (d, J=9 Hz, 2H), 7.73 (br s,1H), 8.00 (s, 1H). MS (DCI) m/z 317 (M+H)⁺.

EXAMPLE 90D2-(2,2,2-Trifluoroethyl)-4-cyclopropylmethoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

A solution of2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(150 mg, 0.47 mmol), cyclopropyl methanol (43 mL, 0.52 mmol) andtriphenylphosphine (124 mg, 0.47 mmol) in freshly distilled THF wasprepared and added dropwise to diethyl azodicarboxylate (75 mL, 0.52mmol) at 0° C. The mixture was allowed to warm to room temperature,stirred for 5 hours and concentrated in vacuo. The residue was purifiedby chromatography on silica gel (95:5 hexanes/ethyl acetate) to providethe product as a colorless oil (yield: 140 mg, 81%). ¹H NMR (300 MHz,CDCl₃) δ 0.22 (m, 2H), 0.48 (m, 2H), 1.6 (m, 1H), 2.53 (s, 3H), 4.26 (d,J=7.5 Hz, 2H), 4.72 (q, J=9 Hz, 2H), 7.32 (d, J=9 Hz, 2H), 7.55 (d, J=9Hz, 2H), 7.87 (s, 1H). MS (DCI/NH₃) m/z 371 (M+H)⁺.

EXAMPLE 90E2-(2,2,2-Trifluoroethyl)-4-cyclopropylmethoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of example 10,substituting2-(2,2,2-trifluoroethyl)-4-cyclopropylmethoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonein place of4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield:130 mg, 85%). mp 133-135° C. ¹H NMR (300 MHz, CDCl₃) δ 0.22 (m, 2H), 0.5(m, 2H), 1.07 (m, 1H), 3.12 (s, 3H), 4.4 (d, J=9 Hz, 2H), 4.83 (q, J=9Hz, 2H), 7.79 (s, 1H), 7.83 (d, J=9 Hz, 2H), 8.07 (d, J=9 Hz, 2H). MS(DCI/NH₃) m/z 403 (M+H)⁺. Anal. calc. for C₁₇H₁₇F₃N₂O₄S: C, 50.74; H,4.25; N, 6.96. Found: C, 50.56; H, 4.09; N, 6.88.

EXAMPLE 912-(2,2,2-Trifluoroethyl)-4-(3-propen-1-oxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 90,substituting 2-propen-1-ol in place of cyclopropylmethanol (yield: 120mg, 77%). mp 121-123° C. ¹H NMR (300 MHz, CDCl₃) δ 3.12 (s, 3H), 4.84(q, J=12 Hz, 2H), 5.07 (d, J=6 Hz, 2H), 5.21 (dd, J=13.5 Hz, 1 Hz, 1H),5.27 (dd, J=15 Hz, 1 Hz, 1H), 5.85 (m, 1H), 7.25 (d, J=9 Hz, 2H), 7.83(s, 1H), 8.06 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 389 (M+H)⁺. Anal. calc.for C₁₆H₁₅F₃N₂O₄S: C, 49.48; H, 3.89; N, 7.21. Found: C, 49.24; H, 3.77;N, 7.16.

EXAMPLE 922-(2,2,2-Trifluoroethyl)-4-(4-fluoro-α-methylbenzyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 90,substituting 4-fluoro-alpha-methylbenzyl alcohol in place ofcyclopropylmethanol (yield: 155 mg, 76%). mp 133-135° C. ¹H NMR (300MHz, CDCl₃) δ 1.57 (d, J=6 Hz, 3H), 3.13 (s, 3H), 4.75 (q, J=7.5 Hz,1H), 4.87 (q, J=7.5 Hz, 1H), 6.34 (q, J=6 Hz, 1H), 6.83 (t, J=9 Hz, 2H),6.98 (dd, J=9 Hz, 6 Hz, 2H), 7.59 (d, J=9 Hz), 7.70 (s, 1H), 8.03 (d,J=9 Hz, 2H). MS (DCI/NH₃) m/z 471 (M+H)⁺. Anal. calc. for C₂₁H₁₈F₄N₂O₄S:C, 53.61; H, 3.85; N, 5.95. Found: C, 53.54; H, 3.73; N, 5.86.

EXAMPLE 932-[4-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A solution of the product from Example 11,4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (344mg, 1.0 mmol), 4-bromothioanisole (812 mg, 4.0 mmol), and copper (70 mg,1.1 mmol) in 20 mL of pyridine was stirred at reflux under a nitrogenatmosphere for 18 hours. After cooling to room temperature, the reactionmixture was diluted with a mixture of water and ethyl acetate. The twolayers were filtered through Celite®, and separated. The organic layerwas washed with 10% aqueous citric acid, with brine, dried over MgSO₄,and filtered. The filtrate was concentrated in vacuo and the residuepurified by column chromatography (silica gel, 93:7dichloromethane/ethyl acetate) to provide the title compound as a foam(yield: 380 mg, 81.5%). ¹H NMR (300 MHz, CDCl₃) δ 2.55 (s, 3H), 3.05 (s,3H), 6.98 (t, J=9 Hz, 2H), 7.22 (dd, J=9 Hz, 6 Hz, 2H), 7.38 (dd, J=8Hz, 2 Hz, 4H), 7.64 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz, 2H), 7.98 (s, 1H).MS (DCI/NH₃) m/z 467 (M+H)⁺. Anal. calc. for C₂₄H₁₉FN₂O₃S₂.0.5H₂O: C,60.63; H, 4.21; N, 5.90. Found: C, 60.72; H, 3.96; N, 5.70.

EXAMPLE 942,5-Bis[4-(methylsulfonyl)phenyl]-4-(4-fluorophenyl)-3(2H)-pyridazinone

The title compound was prepared by oxidizing the product of Example 93,according to the method of Example 10 (yield: 156 mg, 78%). ¹H NMR (300MHz, CDCl₃) δ 3.10 (s, 3H), 3.12 (s, 3H), 7.02 (m, 2H), 7.24 (m, 2H),7.42 (br d, J=9 Hz, 2H), 7.94 (dd, J=9 Hz, 2 Hz, 2H), 8.02 (dd, J=9 Hz,2 Hz, 2H), 8.10 (m, 3H). MS (DCI/NH₃) m/z 499 (M+H)⁺, 516 (M+NH₄)⁺.Anal. calc. for C₂₄H₁₉FN₂O₅S₂.0.5H₂O: C, 56.80; H, 3.94; N, 5.53. Found:C, 56.50; H, 3.88; N, 5.38.

EXAMPLE 952-(3-Methyl-2-thienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to Example 93, substituting2-bromo-3-methylthiophene in place of 4-bromothioanisole (yield: 190 mg,43%). mp 215-217° C. ¹H NMR (300 MHz, CDCl₃) δ 2.21 (s, 3H), 3.08 (s,3H), 6.90 (d, J=9 Hz, 1H), 6.98 (t, J=9 Hz, 2H), 7.24 (dd, J=9 Hz, 6 Hz,3H), 7.41 (d, J=9 Hz, 2H), 7.94 (d, J=9 Hz, 2H), 7.98 (s, 1H). MS(DCI/NH₃) m/z 441 (M+H)⁺, 458 (M+NH₄)⁺. Anal. calc. forC₂₂H₁₇FN₂O₃S₂.0.5H₂O: C, 58.80; H, 4.01; N, 6. 24. Found: C, 58.85; H,3.78; N, 5.99.

EXAMPLE 962-(2-Trifluoromethyl-4-nitrophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to Example 93, substituting2-bromo-5-nitrobenzotrifluoride in place of 4-bromothioanisole (yield:390 mg, 73%); ¹H NMR (300 MHz, CDCl₃) δ 3.08 (s, 3H), 6.98 (t, J=9 Hz,2H), 7.21 (dd, J=9 Hz, 6 Hz, 2H), 7.43 (d, J=9 Hz, 2H), 7.80 (d, J=9 Hz,1H), 7.96 (d, J=9 Hz, 2H), 8.02 (s, 1H), 8.61 (dd, J=9 Hz, 3 Hz, 1H),8.75 (d, J=3 Hz, 1H). MS (DCI/NH₃) m/z 534 (M+H)⁺, 551 (M+NH₄)⁺. Anal.calc. for C₂₄H₁₅F₄N₃O₅S.0.75H₂O: C, 52.70; H, 3.02; N, 7.69. Found: C,52.42; H, 3.04; N, 6.82.

EXAMPLE 972-[3-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone

The title compound was prepared according to Example 93, substituting3-bromothioanisole in place of 4-bromothioanisole (yield: 355 mg, 76%).mp 196° C. ¹H NMR (300 MHz, CDCl₃) δ 2.55 (s, 3H), 3.08 (s, 3H), 6.99(t, J=9 Hz, 2H), 7.23 (dd, J=9 Hz, 6 Hz, 2H), 7.28-7.33 (m, 1H),7.37-7.49 (m, 2H), 7.40 (d, J=9 Hz, 2H), 7.58 (m, 1H), 7.92 (d, J=9 Hz,2H), 7.99 (m, 1H). MS (DCI/NH₃) m/z 467 (M+H)⁺, 484 (M+NH₄)⁺. Anal.calc. for C₂₄H₁₉FN₂O₃S₂: C, 61-80; H, 4.08; N, 6.01. Found: C, 61.56; H,3.93; N, 5.86.

EXAMPLE 982-[3-(Methylsulfonyl)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared by oxidizing the product of Example 97,according to the method of Example 10 (yield: 98 mg, 65.6%). mp 141-142°C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.25 (s, 3H), 3.35 (s, 3H), 7.18 (t, J=9Hz, 2H), 7.32 (dd, J=9 Hz, 6 Hz, 2H), 7.52 (d, J=9 Hz, 2H), 7.83 (t, J=9Hz, 1H), 7.95 (d, J=9 Hz, 2H), 8.05 (m, 1H), 8.25 (t, J=1.5 Hz, 1H),8.33 (s, 1H). MS (DCI/NH₃) m/z 516 (M+NH₄)⁺. Anal. calc. forC₂₄H₁₉FN₂O₅S₂.H₂O: C, 55.81; H, 4.07; N, 5.43. Found: C, 56.24; H, 4.29;N, 5.10.

EXAMPLE 992-(4-Fluorophenyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

4-(4-Chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone isprepared starting with the 2-benzylpyridazinone from Example 53 anddebenzylating the compound according to the method of Example 11.

The title compound was prepared according to the method of Example 93,starting with4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone inplace of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone andsubstituting 1-fluoro-4-iodobenzene in place of 4-bromothioanisole(yield: 245 mg, 54%). mp 195-197° C. ¹H NMR (300 MHz, CDCl₃) δ 3.08 (s,3H), 7.19 (m, 4H), 7.25 (m, 2H), 7.41 (d, J=9 Hz, 2H), 7.70 (m, 2H),7.95 (d, J=9 Hz, 2H), 8.01 (s, 1H). MS (DCI/NH₃) m/z 455 (M+H)⁺, 472(M+NH₄)⁺. Anal. calc. for C₂₃H₁₆ClFN₂O₃S: C, 60.78; H, 3.52; N, 6.17.Found: C, 60.81; H, 3.53; N, 5.93.

EXAMPLE 1002-(5-Chloro-2-thienyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to Example 93, substituting4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone inplace of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone andsubstituting 2-bromo-5-chlorothiophene in place of 4-bromothioanisole(yield: 150 mg, 45%). mp 249-251° C. ¹H NMR (300 MHz, CDCl₃) δ 3.05 (s,3H), 6.92 (d, J=9 Hz, 1H), 7.18 (d, J=9 Hz, 2H), 7.31 (d, J=9 Hz, 2H),7.39 (d, J=9 Hz, 2H), 7.58 (d, J=6 Hz, 1H), 7.94 (d, J=9 Hz, 2 Hz, 2H),8.04 (s, 1H). MS (DCI/NH₃) m/z 477 (M+H)⁺, 494 (M+NH₄)⁺. Anal. calc. forC₂₁H₁₄Cl₂N₂O₃S₂.H₂O: C, 50.9; H, 3.03; N, 5.60. Found: C, 50.5; H, 2.79;N, 5.26.

EXAMPLE 1012-(3-Trifluoromethylphenyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to Example 93, starting with4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone inplace of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone andsubstituting 3-iodobenzotrifluoride in place of 4-bromothioanisole(yield: 210 mg, 59.5%). mp 103-105° C. ¹H NMR (300 MHz, CDCl₃) δ 3.08(s, 3H), 7.18 (d, J=9 Hz, 2H), 7.28 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz,2H), 7.65 (m, 2H), 7.95 (m, 3H), 8.04 (m, 2H). MS (DCI/NH₃) m/z 505(M+H)⁺, 525 (M+NH₄)⁺. Anal. calc. for C₂₄H₁₆ClF₃N₂O₃S: C, 57.14; H,3.17; N, 5.56. Found: C, 56.61; H, 3.28; N, 5.38.

EXAMPLE 1022-(3-Chloro-4-fluorophenyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone

The title compound was prepared according to Example 93, starting with4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(described in Example 99) in place of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone andsubstituting 1-bromo-3-chloro-4-fluorobenzene in place of4-bromothioanisole (yield: 330 mg, 58.8%). mp 205° C. ¹H NMR (300 MHz,CDCl₃) δ 3.10 (s, 3H), 7.17 (d, J=9 Hz, 2H), 7.23-7.31 (m, 1H), 7.28 (d,J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 7.65 (ddd, J=9 Hz, 3 Hz, 1.5 Hz, 1H),7.85 (dd, J=9 Hz, 3 Hz, 1H), 7.93 (d, J=9 Hz, 2H), 8.01 (s, 1H). MS(DCI/NH₃) m/z 489 (M+H)⁺, 508 (M+NH₄)⁺. Anal. calc. for C₂₃H₁₅Cl₂N₂O₃S:C, 56.44; H, 3.17; N, 5.73. Found: C, 56.37; H, 3.19; N, 5.64.

EXAMPLE 1032-(3-Fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to Example 93, substituting1-fluoro-3-iodobenzene in place of 4-bromothioanisole (yield: 310 mg,70.8%). mp 245-247° C. ¹H NMR (300 MHz, CDCl₃) δ 3.08 (s, 3H), 6.98 (t,J=9 Hz, 2H), 7.14 (m, 1H), 7.24 (dd, J=9 Hz, 6 Hz, 2H), 7.40 (m, 2H),7.52 (m, 3H), 7.92 (d, J=9 Hz, 2H), 8.01 (s, 1H). MS (DCI/NH₃) m/z 439(M+H)⁺, 456 (M+NH₄)⁺. Anal. calc. for C₂₃H₁₆F₂N₂O₃S.0.25H₂O: C, 62.34;H, 3.67; N, 6.38. Found: C, 62.33; H, 3.68; N, 6.22.

EXAMPLE 1042-[2-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone

The title compound was prepared according to Example 93, substituting2-bromothioanisole in place of 4-bromothioanisole (yield: 280 mg, 60%).mp 206-208° C. ¹H NMR (300 MHz, CDCl₃) δ 2.49 (s, 3H), 3.08 (s, 3H),6.95 (t, J=9 Hz, 2H), 7.25 (dd, J=9 Hz, 6 Hz, 2H), 7.29-7.51 (m, 4H),7.43 (d, J=9 Hz, 2H), 7.92 (d, J=9 Hz, 3H), 8.01 (s, 1H), 7.98 (s, 1H).MS (DCI/NH₃) m/z 467 (M+H)⁺, 484 (M+NH₄)⁺. Anal. calc. forC₂₄H₁₉FN₂O₃S₂.H₂O: C, 59.50; H, 4.13; N, 5.79. Found: C, 59.62; H, 4.15;N, 5.52.

EXAMPLE 1052-(5-Nitro-2-thienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to Example 93, substituting2-bromo-5-nitrothiophene in place of 4-bromothioanisole (yield: 330 mg,70%). mp 252-253° C. ¹H NMR (300 MHz, CDCl₃) δ 3.06 (s, 3H), 7.05 (t,J=9 Hz, 2H), 7.25 (dd, J=9 Hz, 6 Hz, 2H), 7.40 (d, J=9 Hz, 2H), 7.71 (d,J=6 Hz, 1H), 7.95 (m, 3H), 8.14 (s, 1H). MS (DCI/NH₃) m/z 472 (M+H)⁺,489 (M+NH₄)⁺. Anal. calc. for C₂₁H₁₄FN₃O₅S₂.0.5H₂O: C, 52.50; H, 3.02;N, 8.75. Found: C, 52.79; H, 3.18; N, 8.74.

EXAMPLE 1062-(3,4-Difluorophenyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to Example 93, starting with4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone inplace of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone andsubstituting 1-bromo-3,4-difluorobenzene in place of 4-bromothioanisole(yield: 310 mg, 65.7%). mp 187-188° C. ¹H NMR (300 MHz, CDCl₃) δ 3.09(s, 3H), 7.18 (d, J=9 Hz, 2H), 7.29 (m, 3H), 7.41 (d, J=9 Hz, 2H), 7.52(m, 1H), 7.65 (m, 1H), 7.92 (d, J=9 Hz, 2H), 8.01 (s, 1H). MS (DCI/NH₃)m/z 473 (M+H)⁺, 490 (M+NH₄)⁺. Anal. calc. for C₂₃H₁₅ClF₂N₂O₃S.0.5H₂O:

C, 57.38; H, 3.33; N, 5.82. Found: C, 57.44; H, 3.38; N, 5.52.

EXAMPLE 1072-(3-Benzothienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to Example 93, substituting3-bromobenzothiophene in place of 4-bromothioanisole (yield: 185 mg,41%). mp 265-267° C. ¹H NMR (300 MHz, CDCl₃) δ 3.09 (s, 3H), 7.0 (t, J=9Hz, 2H), 7.27 (dd, J=9 Hz, 6 Hz, 2H), 7.39-7.47 (m, 2H), 7.44 (d, J=9Hz, 2H), 7.75-7.82 (m, 1H), 7.87-7.94 (m, 2H), 7.94 (d, J=9 Hz, 2H),8.05 (s, 1H). MS (DCI/NH₃) m/z 477 (M+H)⁺, 494 (M+NH₄)⁺. Anal. calc. forC₂₅H₁₇FN₂O₃S₂: C, 63.03; H, 3.57; N, 5.88. Found: C, 62.89; H, 3.55; N,5.71.

EXAMPLE 1082-(4-Fluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 108A4-(4-Fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared by treating2-benzyl-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 75) with AlBr₃ in toluene according to the procedure in Example11 (yield: 1.8 g, 95%).

EXAMPLE 108B2-(4-Fluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to Example 93, starting with4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone andsubstituting 1-fluoro-4-iodobenzene in place of 4-bromothioanisole(yield: 60 mg, 53%). mp 83-85° C. ¹H NMR (300 MHz, CDCl₃) δ 3.10 (s,3H), 6.89-7.03 (m, 4H), 7.15 (t, J=9 Hz, 2H), 7.65 (dd, J=9 Hz, 6 Hz,2H), 7.83 (d, J=6 Hz, 2H), 8.07 (d, J=9 Hz, 2H), 8.08 (s, 1H). MS(DCI/NH₃) m/z 455 (M+H)⁺, 472 (M+NH₄)⁺.

EXAMPLE 1092-(3,4-Difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to Example 93, substituting1-bromo-3,4-difluorobenzene in place of 4-bromothioanisole and4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 108A) in place of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 185 mg, 39%). mp 178-180° C. ¹H NMR (300 MHz, CDCl₃) δ 3.11 (s,3H), 6.89-7.04 (m, 4H), 7.45-7.52 (m, 1H), 7.45-7.52 (m, 1H), 7.61 (dt,J=6 Hz, 3 Hz, 1H), 7.82 (d, J=9 Hz, 2H), 8.07 (d, J=9 Hz, 2H), 8.08 (s,1H). MS (DCI/NH₃) m/z 473 (M+H)⁺, 490 (M+NH₄)⁺. Anal. calc. forC₂₃H₁₅F₃N₂O₄S.0.5H₂O: C, 57.38; H, 3.33; N, 5.83. Found: C, 57.17; H,3.13; N, 5.62.

EXAMPLE 1102-(3-Bromophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to Example 93, substituting1,3-dibromobenzene in place of 4-bromothioanisole and4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 108A) in place of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 260 mg, 50.5%). mp 208-210° C. ¹H NMR (300 MHz, CDCl₃) δ 3.09(s, 3H), 6.89-7.04 (m, 4H), 7.34 (t, J=9 Hz, 1H), 7.53 (br d, J=9 Hz,1H), 7.64 (br d, J=9 Hz, 1H), 7.82 (d, J=9 Hz, 2H), 7.87 (t, J=1.5 Hz,1H), 8.08 (d, J=9 Hz, 2H), 8.09 (s, 1H). MS (DCI/NH₃) m/z 517 (M+H)⁺,534 (M+NH₄)⁺. Anal. calc. for C₂₃H₁₆BrFN₂O₄S: C, 53.7; H, 3.11; N, 5.45.Found: C, 53.46; H, 2.88; N, 5.18.

EXAMPLE 1112-(3,5-Difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to Example 93, substituting1-bromo-3,4-difluorobenzene in place of 4-bromothioanisole and4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 108A) in place of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 175 mg, 37%). mp 209-211° C. ¹H NMR (300 MHz, CDCl₃) δ 3.10 (s,3H), 6.85 (tt, J=9 Hz, 3 Hz, 1H), 6.90-7.04 (m, 4H), 7.38 (dd, J=9 Hz, 3Hz, 2H), 7.81 (d, J=9 Hz, 2H), 8.07 (d, J=9 Hz, 2H), 8.10 (s, 1H). MS(DCI/NH₃) m/z 473 (M+H)⁺, 490 (M+NH₄)⁺. Anal. calc. for C₂₃H₁₅N₂O₄S.H₂O:C, 58.47; H, 3.18; N, 5.94. Found: C, 58.31; H, 3.15; N, 5.82.

EXAMPLE 1122-(3-Chlorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to Example 93, substituting1-bromo-3-chlorobenzene in place of 4-bromothioanisole and4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 108A) in place of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 25 mg, 5.3%). mp 211-213° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.30(s, 3H), 7.15 (d, J=9 Hz, 4H), 7.51-7.64 (m, 3H), 7.71-7.75 (m, 1H),7.91 (d, J=9 Hz, 2H), 8.06 (d, J=9 Hz, 2H), 8.41 (s, 1H). MS (DCI/NH₃)m/z 471 (M+H)⁺, 488 (M+NH₄)⁺. Anal. calc. for C₂₃H₁₆ClFN₂O₄S.0.5H₂O: C,57.62; H, 3.44; N, 5.85. Found: C, 57.62; H, 3.52; N, 5.48.

EXAMPLE 1132-(4-Nitrobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 4-nitrobenzyl bromide in place of 4-fluorobenzyl bromide(yield: 164 mg, 58.9%). mp 183-184° C. ¹H NMR (300 MHz, CDCl₃) δ 3.05(s, 3H), 5.47 (s, 2H), 6.96 (t, J=9 Hz, 2H), 7.16 (dd, J=9 Hz, 3 Hz,2H), 7.32 (d, J=9 Hz, 2H), 7.70 (d, J=9 Hz, 2H), 7.87 (s, 1H), 7.88 (d,J=9 Hz, 2H), 8.22 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 480 M+H)⁺, m/z 497(M+NH₄)⁺. Anal. calc. for C₂₄H₁₈FN₃O₅S: C, 60.12; H, 3.78; N, 8.76.Found: C, 59.89; H, 3.83; N, 8.61.

EXAMPLE 1142-(4-Acetoxybenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 4-(chloromethyl)phenyl acetate in place of 4-fluorobenzylbromide (yield: 220 mg, 76.9%). mp 172-174° C. ¹H NMR (300 MHz, CDCl₃) δ2.30 (s, 3H), 3.05 (s, 3H), 5.38 (s, 2H), 6.95 (t, J=9 Hz, 2H), 7.06 (d,J=9 Hz, 2H), 7.16 (dd, J=9 Hz, 5 Hz, 2H), 7.31 (d, J=9 Hz, 2H), 7.60 (d,J=9 Hz, 2H), 7.81 (s, 1H), 7.87 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 510(M+NH₄)⁺. Anal. calc. for C₂₆H₂₁FN₂O₅S: C, 63.40; H, 4.30; N, 5.69.Found: C, 63.28; H, 4.41; N, 5.39.

EXAMPLE 1152-(4-Hydroxybenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A solution of2-(4-acetoxybenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(0.2 g, 4.06 mmol) (Example 114) in THF (20 mL) was treated with asolution of lithium hydroxide monohydrate (0.05 g, 1.22 mmol) in water(5 mL). Methanol (2 mL) was added to provide a homogeneous solutionwhich was stirred at room temperature overnight. The reaction mixturewas then acidified with 10% aqueous citric acid and extracted with ethylacetate. The ethyl acetate layer was dried over MgSO₄ and filtered. Thefiltrate was concentrated in vacuo to provide a white foam which waspurified by column chromatography (silica gel, 65:35 hexanes/ethylacetate). Product fractions were combined and concentrated in vacuo. Theresidue was crystallized from ethyl acetate/hexanes (yield: 195 mg,70%). mp 225-226° C. ¹H NMR (300 MHz, CDCl₃) δ 3.05 (s, 3H), 4.86 (s,1H), 5.33 (s, 2H), 6.80 (d, J=8.5 Hz, 2H), 6.95 (t, J=9 Hz, 2H), 7.15(dd, J=9 Hz, 5 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H),7.83 (s, 1H), 7.87 (d, J=8.5 Hz, 2H). MS (DCI/NH₃) m/z 451 (M+H)⁺. Anal.calc. for C₂₄H₁₉FN₂O₄S: C, 63.99; H, 4.25; N, 6.22. Found: C, 63.73; H,4.16; N, 6.11.

EXAMPLE 1162-(3-Nitrobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20;substituting 3-nitrobenzyl bromide in place of 4-fluorobenzyl bromide(yield: 195 mg, 70%). mp 156-157° C. ¹H NMR (300 MHz, CDCl₃) δ 3.05 (s,3H), 5.48 (s, 2H), 6.96 (t, J=9 Hz, 2H), 7.16 (dd, J=9 Hz, 5 Hz, 2H),7.33 (d, J=8.5 Hz, 2H), 7.54 (t, J=7 Hz, 1H), 7.88 (s, 1H), 7.90 (d,J=8.5 Hz, 2H), 8.19 (br d, J=7 Hz, 1H), 8.37 (t, J=1.7 Hz, 1H). MS(DCI/NH₃) m/z 480 (M+H)⁺, m/z 497 (M+NH₄)⁺. Anal. calc. forC₂₄H₁₈FN₃O₅S: C, 60.12; H, 3.78; N, 8.76. Found: C, 59.98; H, 3.73; N,8.67.

EXAMPLE 1172-(3,424-Trifluoro-3-butenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone

The title compound was prepared according to the method of Example 20,substituting 4-bromo-1,1,2-trifluoro-1-butene in place of 4-fluorobenzylbromide (yield: 38 mg, 14.5%). mp 131-132° C. ¹H NMR (300 MHz, CDCl₃) δ2.92 (br d, J=21.7 Hz, 2H), 3.06 (s, 3H), 4.47 (t, J=6.6 Hz, 2H), 6.98(t, J=9 Hz, 2H), 7.17 (dd, J=9 Hz, 5 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H),7.85 (s, 1H), 7.89 (d, J=8.5 Hz, 2H). MS (DCI/NH₃) m/z 453 (M+H)⁺, m/z470 (M+NH₄)⁺. Anal. calc. for C₂₁H₁₆F₄N₂O₃S: C, 55.75; H, 3.56; N, 6.19.Found: C, 55.63; H, 3.62; N, 6.10.

EXAMPLE 1182-(2-Hexynyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 1-chloro-2-hexyne in place of 4-fluorobenzyl bromide(yield: 170 mg, 69%). mp 79-80° C. ¹H NMR (300 MHz, CDCl₃) δ 0.99 (t,J=7.5 Hz, 3H), 1.56 (h, J=7.5 Hz, 2H), 2.21 (m, 2H), 3.06 (s, 3H), 5.01(t, J=3 Hz, 2H), 6.96 (t, J=9 Hz, 2H), 7.18 (dd, J=9 Hz, 6 Hz, 2H), 7.34(d, J=9 Hz, 2H), 7.88 (s, 1H), 7.89 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z425 (M+H)⁺. Anal. calc. for C₂₃H₂₁FN₂O₃S: C, 65.07; H, 4.98; N, 6.59.Found: C, 64.87; H, 4.90; N, 6.58.

EXAMPLE 1192-(3,3-Dichloro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)-phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting 1,1,3-trichloropropene in place of 4-fluorobenzyl bromide(yield: 1.15 g, 68%). mp 184-185° C. ¹H NMR (300 MHz, DMSO-d₆) δ 4.39(d, J=7.5 Hz, 2H), 6.43 (t, J=7.5 Hz, 1H), 7.14 (t, J=9 Hz, 2H), 7.23(dd, J=9 Hz, 6 Hz, 2H), 7.38 (d, J=9 Hz, 2H), 7.43 (s, 2H), 7.73 (d, J=9Hz, 2H), 8.11 (s, 1H). MS (DCI/NH₃) m/z 454 (M+H)⁺. Anal. calc. forC₁₉H₁₄Cl₂F₄N₃O₃S: C, 50.23; H, 3.1; N, 9.24. Found: C, 50.28; H, 3.29;N, 9.19.

EXAMPLE 1202-Cyclohexyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20substituting cyclohexyl bromide in place of 4-fluorobenzyl bromide(yield: 163 mg, 76%). mp 169-171° C. ¹H NMR (DMSO-d₆, 300 MHz) 6.23 (m,1H), 1.41 (m, 2H), 1.71 (m, 3H), 1.87 (m, 4H), 3.23 (s, 3H), 4.85 (m,1H), 7.11 (m, 2H), 7.22 (m, 2H), 7.46 (d, J=9 Hz, 2H), 7.85 (d, J=9 Hz,2H), 8.11 (s, 1H). MS (DCI/NH₃) m/z 427 (M+H)⁺ and m/z 444 (M+NH₄)⁺.Anal. calc. for C₂₃H₂₃FN₂O₃S.0.5H₂O: C, 63.43; H, 5.55; N, 6.43. Found:C, 63.25; H, 5.28; N, 6.28.

EXAMPLE 1212-Cyclopentyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting cyclopentyl bromide in place of 4-fluorobenzyl bromide(yield: 165 g, 80%). mp 191-193° C. ¹H-NMR (DMSO-d₆, 300 MHz) δ 1.67 (m,2H), 1.85 (m, 4H), 2.05 (m, 2H), 3.23 (s, 3H), 5.36 (m, 1H), 7.12 (t,J=9 Hz, 2H), 7.22 (m, 2H), 7.45 (d, J=9 Hz, 2H), 7.85 (d, J=9 Hz, 2H),8.13 (s, 1H). MS (DCI/NH₃) m/z 413 (M+H)⁺ and m/z 430 (M+NH₄)⁺. Anal.calc. for C₂₂H₂₁FN₂O₃S.0.5H₂O: C, 62.69; H, 5.26; N, 6.57. Found: C,62.53; H, 4.93; N, 6.50.

EXAMPLE 1222-Cyclobutyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 20,substituting cyclobutyl bromide in place of 4-fluorobenzyl bromide(yield: 270 g, 68%). mp 202-203° C. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.85 (m,2H), 2.32 (m, 2H), 2.50 (m, 2H), 5.40 (quintet, J=7 Hz, 1H), 7.11 (t,J=9 Hz, 2H), 7.21 (m, 2H), 7.47 (d, J=9 Hz, 2H), 7.86 (d, J=9 Hz, 2H),8.16 (s, 1H). MS (DCI/NH₃) m/z 399 (M+H)⁺ and m/z 416 (M+NH₄)⁺. Anal.calc. for C₂₁H₁₉FN₂O₃S.0.75H₂O: C, 61.22; H, 5.01; N, 6.80. Found: C,61.19; H, 4.62; N, 6.73.

EXAMPLE 1232-(3-Methyl-2-butenyl)-4-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)pyridazinone

2-Benzyl-4-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone,prepared according to the method of Example 68, was N-debenzylatedaccording to the method of Example 11. The intermediate was N-alkylatedaccording to the method of Example 20, substituting1-bromo-3-methyl-2-butene in place of 4-fluorobenzyl bromide, to providethe title compound (yield: 50 mg, 30%). mp 134-136° C. ¹H NMR (300 MHz,CDCl₃) δ 1.79 (s, 3H), 1.86 (s, 3H), 4.78 (s, 2H), 4.85 (d, J=7.5 Hz,2H), 5.48 (t, J=6 Hz, 1H), 6.96 (t, J=9 Hz, 2H), 7.18 (dd, J=9 Hz, 6 Hz,2H), 7.28 (d, J=9 Hz, 2H), 7.83 (s, 1H), 7.85 (d, J=9 Hz, 2H). MS(DCI/NH₃) m/z 414 (M+H)⁺. Anal. calc. for C₂₁H₂₀FN₃O₃S: C, 61; H, 4.87;N, 10.16. Found: C, 60.98; H, 4.66; N, 9.95.

EXAMPLE 1242-(2,4-Difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone,prepared according to the method of Example 68, was N-debenzylatedaccording to the method of Example 11. The intermediate was N-alkylatedaccording to the method of Example 20, substituting2,4-difluorobenzylbromide in place of 4-fluorobenzyl bromide to providethe title compound (yield: 65 mg, 24%). mp 236-238° C. ¹H NMR (300 MHz,CDCl₃) δ 4.78 (s, 2H), 5.43 (s, 2H), 6.88 (m, 2H), 6.97 (t, J=9 Hz, 2H),7.18 (dd, J=9 Hz, 6 Hz, 2H), 7.38 (d, J=9 Hz, 2H), 7.55 (m, 1H), 7.85(s, 1H), 7.86 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 472 (M+H)⁺. Anal. calc.for C₂₃H₁₆F₃N₃O₃S: C, 58.59; H, 3.42; N, 8.91. Found: C, 58.44; H, 3.47;N, 8.72.

EXAMPLE 1252-(Pentafluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]—3(2H)-pyridazinone

The title compound was prepared according to the method of Example 124,substituting 2,3,4,5,6-pentafluorobenzyl bromide in place of1-bromo-3-methyl-2-butene (yield: 105 mg, 35%). mp 201-203° C. ¹H NMR(300 MHz, CDCl₃) δ 4.8 (s, 2H), 5.5 (s, 2H), 6.98 (t, J=9 Hz, 2H), 7.18(dd, J=9 Hz, 6 Hz, 2H), 7.28 (d, J=9 Hz, 2H), 7.32 (s, 1H), 7.37 (d, J=9Hz, 2H). MS (DCI/NH₃) m/z 526 (M+H)⁺. Anal. calc. for C₂₃H₁₃F₆N₃O₃S: C,52.57; H, 2.49; N, 7.99. Found: C, 52.66; H, 2.68; N, 7.8.

EXAMPLE 1262-(3-Cyclohexenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 124,substituting 3-bromocyclohexane in place of 1-bromo-3-methyl-2-butene(yield: 30 mg, 10%). mp 206-208° C. ¹H NMR (300 MHz, CDCl₃) δ 1.75-1.85(m, 3H), 2.1-2.3 (m, 3H), 4.8 (s, 2H), 5.75 (m, 2H), 6.1 (m, 1H), 6.97(t, J=9 Hz, 2H), 7.20 (dd, J=9 Hz, 6 Hz, 2H), 7.28 (d, J=9 Hz, 2H), 7.86(d, J=9 Hz, 2H), 7.90 (s, 1H). MS (DCI/NH₃) m/z 426 (M+H)⁺. Anal. calc.for C₂₂H₂₀FN₃O₃S: C, 62.10; H, 4.73; N, 9.87. Found: C, 61.27; H, 4.75;N, 9.56.

EXAMPLE 1272-(3,4-Difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)Phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 124,substituting 3,4-difluorobenzyl bromide in place of1-bromo-3-methyl-2-butene and running the reaction in DMSO instead ofDMF to prevent formation of byproducts (yield: 210 mg, 62%). mp 253-255°C. ¹H NMR (300 MHz, DMSO-d₆) δ 5.33 (s, 2H), 7.13 (t, J=9 Hz, 2H), 7.22(dd, J=9 Hz, 6 Hz, 2H), 7.28 (m, 1H), 7.39 (d, J=9 Hz, 2H), 7.42 (s,2H), 7.47 (m, 2H), 7.73 (d, J=9 Hz, 2H), 8.12 (s, 1H). MS (DCI/NH₃) m/z472 (M+H)⁺. Anal. calc. for C₂₃H₁₆F₃N₃O₃S: C, 58.59; H, 3.42; N, 8.91.Found: C, 58.05; H, 3.55; N, 8.49.

EXAMPLE 1282-(2,3-Dihydro-1H-inden-2-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A solution of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (172mg, 0.5 mmol), prepared in Example 11, 2-indanol (67 mg, 0.5 mmol) andPh₃P (262 mg, 1 mmol) in toluene (20 mL) and ethyl acetate (5 mL) wasprepared and added dropwise a solution of DIAD (0.2 mL, 1 mmol) intoluene (10 mL). The mixture was stirred at room temperature for 6 hoursand concentrated in vacuo. The residue was chromatographed (silica gel,19:1 CH₂Cl₂-ethyl acetate) to provide 200 mg of product (contaminatedwith reduced DIAD). A second column chromatography (hexanes-ethylacetate 1:1) furnished the title product (yield: 170 mg, 74%). mp97-100° C. ¹H NMR (DMSO-d₆, 300 MHz) δ 3.22 (s, 3H), 3.32 (m, 2H), 3.44(dd, J=9 Hz and 15 Hz, 2H), 5.83 (m, 1H), 7.25 (m, 4H), 7.34 (m, 4H),7.46 (d, J=9 Hz, 2H), 7.85 (d, J=9 Hz, 2H), 8.06 (s, 1H). MS (DCI/NH₃)m/z 461 (M+H)⁺ and m/z 478 (M+NH₄)⁺.

EXAMPLE 1292-(2,3-Dihydro-1H-inden-1-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 128substituting 1-indanol in place of 2-indanol (yield: 110 mg, 48%). mp128-130° C. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.40 (m, 1H), 2.60 (m, 1H), 3.00(m, 1H), 3.22 (s+m, 4H), 6.60 (dd, J=9 Hz, 6 Hz, 1H), 7.16 (m, 4H), 7.27(m, 4H), 7.47 (d, J=9 Hz, 2H), 7.85 (d, J=9 Hz, 2H), 8.02 (s, 1H). MS(DCI/NH₃) m/z 461 (M+H)⁺ and m/z 478 (M+NH₄)⁺.

EXAMPLE 1302-(4-Tetrahydro-2H-pyran-4-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 128substituting 4-tetrahydropyranyl in place of 2-indanol (yield: 140 g,65%). mp 230-231° C. ¹H NMR (300 MHz, DMSO-d₆) δ 1.75 (m, 2H), 1.93 (m,2H), 3.14 (s, 3H), 3.46 (m, 2H), 3.93 (m, 2H); 5.02 (m, 1H), 7.05 (t,J=9 Hz, 2H), 7.15 (m, 2H), 7.40 (d, J=9 Hz, 2H), 7.80 (d, J=9 Hz, 2H),8.08 (s, 1H). MS (APCI−) m/z 428 (M−H)- and m/z 463 (M+Cl)⁻. Anal. calc.for C₂₂H₂₁FN₂O₄S.1.25H₂O: C, 58.59; H, 5.25; N, 6.21. Found: C, 58.31;H, 4.75; N, 6.05.

EXAMPLE 1312-(2-Methylcyclopentyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 128substituting 2-methylcyclopentanol in place of 2-indanol (yield: 230 g,86%). mp 180-181° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.75 (d, J=7 Hz, 3H),1.60 (m, 2H), 1.89 (m, 2H), 2.10 (m, 1H), 2.21 (m, 1H), 2.40 (m, 1H),3.23 (s, 3H), 5.37 (q, J=7 Hz, 1H), 7.12 (t, J=9 Hz, 2H), 7.21 (m, 2H),7.47 (d, J=9 Hz, 2H), 7.86 (d, J=9 Hz, 2H), 8.11 (s, 1H). MS (APCI+) m/z427 (M+H)⁺ and (APCI−) m/z 461 (M+Cl)⁻. Anal. calc. for C₂₃H₂₃FN₂O₃S: C,64.77; H, 5.43; N, 6.56. Found: C, 64.71; H, 5.34; N, 6.28.

EXAMPLE 1322-(2-Adamantyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 128substituting 2-adamantanol in place of 2-indanol, (yield: 75 g, 25%) mp195-197° C. ¹H NMR (300 MHz, DMSO-d₆) δ 1.60 (m, 2H), 1.77 (m, 2H), 1.94(m, 6H), 2.35 (m, 4H), 3.23 (s, 3H), 4.83 (m, 1H), 7.11 (t, J=9 Hz, 2H),7.22 (m, 2H), 7.47 (d, J=9 Hz, 2H), 7.87 (d, J=9 Hz, 2H), 8.11 (s, 1H).MS (APCI+) m/z 479 (M+H)⁺ and (APCI−) m/z 478 (M−H)⁻, m/z 513 (M+Cl)⁻.Anal. calc. for C₂₇H₂₇FN₂O₃S.0.25H₂O: C, 67.13; H, 5.73; N, 5.79. Found:C, 67.06; H, 5.76; N, 5.06.

EXAMPLE 1332-(3-Methylcyclopentyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 128substituting 3-methylcyclopentanol in place of 2-indanol (yield: 155 g,73%). mp 169-171° C. ¹H NMR (300 MHz, DMSO-d₆) δ 1.05 (dd, 2:1, 3H),1.24 (m, 1H), 1.63 (m, 1H), 2.00 (m, 3H), 2.22 (m, 2H), 3.23 (s, 3H),5.43 (m, 1H), 7.1 (t, J=9 Hz, 2H), 7.21 (m, 2H), 7.46 (d, J=9 Hz, 2H),7.86 (d, J=9 Hz, 2H), 8.12 (two s, 2:1, 1H). MS (APCI+) m/z 27 (M+H)⁺and (APCI−) m/z 426 (M−H)—, m/z 461 (M+Cl)⁻. Anal. calc. forC₂₇H₂₇FN₂O₃S.0.25H₂O: C, 64.09; H, 5.49; N, 6.49. Found: C, 64.27; H,5.62; N, 6.46.

EXAMPLE 1342-(1-Methylcyclopentyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A solution of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (206mg, 0.6 mmol), prepared according to the method of Example 11,1-methyl-1-cyclopentanol (60 mg, 0.6 mmol), DMAP (18 mg, 0.12 mmol) andPh₃P (262 mg, 1 mmol) in toluene (30 mL) in ethyl acetate (5 mL) wasprepared and added dropwise to a solution of DIAD (0.2 mL, 1 mmol) in 10mL of toluene. The mixture was stirred at room temperature for 6 hoursand then concentrated in vacuo. The residue was chromatographed (silicagel, 19:1 CH₂Cl₂-ethyl acetate) to provide 80 mg of product(contaminated with reduced DIAD). A second column chromatography(hexanes-ethyl acetate 1:1) furnished the title product, (yield: 50 mg,19%). mp 107-110° C. ¹H NMR (DMSO-d₆, 300 MHz) δ 1.55 (s, 3H), 1.70 (m,4H), 2.08 (m, 2H), 2.32 (m, 2H), 3.22 (s, 3H), 7.10 (t, J=9 Hz, 2H),7.20 (m, 2H), 7.45 (d, J=9 Hz, 2H), 7.86 (d, J=9 Hz, 2H), 8.03 (s, 1H).MS (APCI+) m/z 427 (M+H)⁺ and (APCI−) m/z 426 (M−H)⁻, m/z 461 (M+Cl)⁻.

EXAMPLE 1352-(3,4-Difluorophenyl)-4-(4-fluoro-3-vinylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 135A 5-Bromo-2-fluorostyrene

A mixture of methyltriphenylphosphonium bromide (2.14 g, 6 mmol) andpotassium t-butoxide (672 mg, 6 mmol) in 50 mL of THF was refluxed for30 minutes under N₂ and then cooled to room temperature.5-Bromo-2-fluorobenzaldehyde (1.02 g, 5 mmol) was added and theresulting mixture was refluxed for 2 hours (until the TLC showed thedisappearance of starting aldehyde). The reaction was concentrated invacuo and partitioned between water and ethyl acetate. The acetate layerwas washed with water and brine. The solution was dried over MgSO₄ andconcentrated in vacuo. The residue was purified by chromatography(silica gel, 15:1 hexanes-diethyl ether) to provide 900 mg (90%) of5-bromo-2-fluorostyrene.

EXAMPLE 135B2-(3,4-Difluorophenyl)-4-(4-fluoro-3-vinylphenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

The bromo-styrene compound, Example 135A, in 10 mL of THF was addeddropwise to a heated mixture of magnesium turnings (120 mg, 5 mmol) anda few drops of 1,2-dibromoethane in THF (20 mL) at a rate to maintain agentle reflux. The mixture was refluxed for the next 30 minutes andcooled to room temperature. The Grignard reagent solution was cooled to−78° C. and added, dropwise, to a solution of2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(540 mg, 1.5 mmol) in THF (20 mL). The reaction mixture was allowed towarm to room temperature for 12 hours. Afterwards, a saturated solutionof NH₄Cl was added and the mixture was extracted with ethyl acetate toprovide 320 mg of crude sulfide.

EXAMPLE 135C2-(3,4-Difluorophenyl)-4-(4-fluoro-3-vinylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The sulfide, Example 135B, was dissolved in CH₂Cl₂ (20 mL) and at 0° C.was treated with 30% CH₃CO₃H in CH₃CO₂H (0.5 mL). After 1.5 hours 10%NaHCO₃ was added and the mixture extracted with CH₂Cl₂. The extract wasconcentrated in vacuo and the residue purified by chromatography (silicagel, 1:1 hexanes-ethyl acetate) to provide the title compound (yield:270 mg, 37%). ¹H NMR (DMSO-d₆, 300 MHz) δ 3.22 (s, 3H), 5.37 (d, J=12Hz, 1H), 5.65 (d, J=18 Hz, 1H), 6.77 (dd, J=12 Hz and 18 Hz, 1H), 7.15(m, 2H), 7.57 (m, 5H), 7.90 (m, 3H), 8.28 (s, 1H). MS (APCI+) m/z 483(M+H)⁺ and (APCI−) m/z 517 (M+Cl)⁻. Anal. calc. forC₂₅H₁₇F₃N₂O₃S.0.5H₂O: C, 61.09; H, 3.69; N, 5.69. Found: C, 61.04; H,3.71; N, 5.34.

EXAMPLE 1362-(3,4-Difluorophenyl)-4-(6-methyl-3-heptenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A Grignard, prepared as described in Example 135, substituting2-(2-bromoethyl)-1,3-dioxane (586 mg, 3 mmol) in place of5-bromo-2-fluorostyrene, was added to a solution of2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(720 mg, 2 mmol) in THF (30 mL) at −78° C. The mixture was left at roomtemperature for 14 hours, quenched with a saturated solution of NH₄Cland extracted with ethyl acetate to obtain 900 mg of crude sulfide.

The intermediate sulfide product was dissolved in CH₂Cl₂ (10 mL) andtreated at 0° C. with 33% solution of CH₃CO₃H in CH₃CO₂H (0.7 mL) for 1hour. The mixture was concentrated in vacuo and the residue waspartitioned between saturated NaHCO₃ and ethyl acetate. The acetatelayer was dried over MgSO₄ and concentrated in vacuo to provide 950 mgof crude sulfonyl derivative.

The sulfonyl compound, prepared above, was dissolved in acetone (50 mL)and treated with 2 N HCl (10 mL). The resulting mixture was refluxed for16 hours and concentrated in vacuo. The residue was extracted with ethylacetate to provide 900 mg of2-(3,4-difluorophenyl)-4-(2-formylethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(crude aldehyde, contaminated with some unreacted starting dioxanederivative).

A mixture of isoamyltriphenylphosphonium bromide (414 mg, 1 mmol) andpotassium t-butoxide (112 mg, 1 mmol) in toluene (25 mL) was refluxedfor 30 minutes and then cooled to room temperature. The crude aldehydewas added and the mixture was refluxed for 14 hours. The reactionmixture was then cooled to room temperature and concentrated in vacuo.The residue was dissolved in ethyl acetate and was washed with water,10% citric acid, brine, dried over MgSO₄ and concentrated in vacuo.Purification by column chromatography (silica gel, 1:1 hexanes-ethylacetate) provided the title compound as an oil (yield: 120 mg, 13%). ¹HNMR (300 MHz, DMSO-d₆) δ 0.74 (d, J=7 Hz, 6H), 1.44 (m, 1H), 1.70 (t,J=7 Hz, 2H), 2.22 (m, 2H), 2.54 (m, 2H); 3.30 (s, 3H), 5.29 (m, 2H),7.51 (m, 1H), 7.63 (m, 1H), 7.74 (d, J=9 Hz, 2H), 7.82 (m, 1H), 8.02 (s,1H), 8.10 (d, J=9 Hz, 2H). MS (APCI+) m/z 473 (M+H)⁺ and (APCI−) m/z 471(M−H)⁻, m/z 507 (M+Cl)⁻. Anal. calc. for C₂₅H₂₆F₂N₂O₃S: C, 63.54; H,5.54; N, 5.92. Found: C, 63.74; H, 5.67; N, 5.58.

EXAMPLE 1372-(3,4-Difluorophenyl)-4-(3-cyclopropylidenenpropyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 136substituting cyclopropyltriphenylphosphonium bromide in place ofisoamyltriphenylphosphonium bromide (yield: 55 mg, 12%). mp 128-129° C.¹H NMR (300 MHz, DMSO-d₆) δ 0.81 (m, 2H), 0.97 (m, 2H), 2.34 (m, 2H),2.65 (m, 2H), 3.32 (s, 3H), 5.64 (m, 1H), 7.52 (m, 1H), 7.63 (m, 1H),7.73 (d, J=9 Hz, 2H), 7.81 (m, 1H), 8.02 (s, 1H), 8.10 (d, J=9 Hz, 2H).MS (APCI+) m/z 443 (M+H)⁺ and (APCI−) m/z 441 (M−H)—, m/z 477 (M+Cl)⁻.Anal. calc. for C₂₃H₂₀F₂N₂O₃S.0.5H₂O: C, 61.18; H, 4.68; N, 6.20. Found:C, 61.48; H, 4.60; N, 6.02.

EXAMPLE 1382-(3,4-Difluorophenyl)-4-(5-methyl-3-hexyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound, an oil, was prepared according to the method ofExample 136 substituting isobutyltriphenylphosphonium bromide in placeof isoamyltriphenylphosphonium bromide (yield: 170 mg, 74%). ¹H NMR (300MHz, DMSO-d₆) δ 0.75 (d, J=7 Hz, 6H), 2.22 (m, 3H), 2.54 (m, 2H), 3.32(s, 3H), 5.12 (m, 2H), 7.52 (m, 1H), 7.60 (m, 1H), 7.72 (d, J=9 Hz, 2H),7.80 (m, 1H), 8.02 (s, 1H), 8.10 (d, J=9 Hz, 2H). MS (APCI+) m/z 459(M+H)⁺ and (APCI−) m/z 457 (M−H)—, m/z 493 (M+Cl)⁻. Anal. calc. forC₂₄H₂₄F₂N₂O₃S: C, 62.86; H, 5.27; N, 6.10. Found: C, 62.57; H, 5.32; N,5.81.

EXAMPLE 1392-(3,4-Difluorophenyl)-4-(5-methylhexyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound, an oil, was prepared according to the method ofExample 135B, substituting 5-methylhexylmagnesium bromide for3-fluoro-4-vinylphenylmagnesium bromide, (yield: 28 mg, 10%). ¹H NMR(300 MHz, DMSO-d₆) δ 0.77 (d, J=7 Hz, 6H), 0.88 (m, 1H), 1.03 (m, 2H),1.20 (m, 1H), 1.46 (m, 5H), 3.32 (s, 3H), 7.52 (m, 1H), 7.62 (m, 1H),7.75 (d, J=9 Hz, 2H), 7.82 (m, 1H), 8.02 (s, 1H), 8.11 (d, J=9 Hz, 2H).MS (APCI+) m/z 461 (M+H)⁺ and (APCI) m/z 459 (M−H)—, m/z 495 (M+Cl)⁻.

EXAMPLE 1402-(3-Chloro-1-methyl-2E-propenyl)-4-(4-fluoro-phenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 124,substituting 1,3-dichloro-1-butene in place of 2,4-difluorobenzylbromide (yield: 55 mg, 30). mp 152-154° C. ¹H NMR (300 MHz, CDCl₃) δ4.71 (dt, J=15 Hz, 7.5 Hz, 2H), 2.28 (d, J=1.5 Hz, 3H), 4.8 (s, 2H),4.99 (d, J=1 Hz, 1H), 5.02 (d, J=1 Hz, 1H), 5.85 (td, J=4 Hz, 1 Hz, —H),6.98 (t, J=9 Hz, 2H), 7.19 (dd, J=9 Hz, 6 Hz, 2H), 7.28 (d, J=9 Hz, 2H),7.86 (s, 1H), 7.87 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 434 (M+H)⁺. Anal.calc. for C₂₀H₁₇ClFN₃O₃S: C, 55.36; H, 3.94; N, 9.68. Found: C, 54.99;H, 3.83; N, 9.34.

EXAMPLE 1412-(2,3,3-Trifluoro-2-propen-1-yl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 124,substituting 1-methylsulfonyloxy-2,3,3-trifluoro-2-propene (mesylate),prepared in Example 88, in place of 2,4-difluorobenzyl bromide (yield:10 mg, 4%). mp 173-175° C. ¹H NMR (300 MHz, CDCl₃) δ 4.39 (s, 2H), 5.09(ddd, J=26 Hz, J=3 Hz, J=1 Hz, 2H), 6.98 (t, J=9 Hz, 2H), 7.19 (dd, J=9Hz, J=6 Hz, 2H), 7.29 (d, J=9 Hz, 2H), 7.78 (s, 1H), 7.78 (d, J=9 Hz,2H). MS (DCI/NH₃) m/z 440 (M+H)⁺, MS (F, high res.) m/z calc. forC₁₉H₁₄F₄N₃O₃S: 440.0692 (M+H)⁺. Found: 440.0695 (M+H)⁺, (0.7 ppm error).

EXAMPLE 1422-(1,1,2-Trifluoro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was isolated from the same reaction mixture (Example141) that was used to prepare 2(2,3,3-trifluoro-2-propen-1-yl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone(The title product is a result of an SN2′ attack.) (yield: 50 mg, 20%).mp 230-232° C. ¹H NMR (300 MHz, CDCl₃) δ 4.7 (s, 2H), 5.28 (dd, J=15 Hz,4.5 Hz, 1H), 5.39 (dd, J=45 Hz, 4.5 Hz, 1H), 6.98 (t, J=9 Hz, 2H), 7.19(dd, J=9 Hz, 6 Hz, 2H), 7.31 (d, J=9 Hz, 2H), 7.9 (d, J=9 Hz, 2H), 7.92(s, 1H), MS (DCI/NH₃) m/z 440 (M+H)⁺. Anal. calc. for C₁₉H₁₃F₄N₃O₃S: C,51.93; H, 2.98; N, 9.56. Found: C, 51.88; H, 3.01; N, 9.15.

EXAMPLE 1432-(3,3-Difluoro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 124,substituting 1,3-dibromo-1,1-difluoropropane in place of2,4-difluorobenzyl bromide and employing 5 equivalents of potassiumcarbonate (yield: 220 mg, 65%). mp 191-194° C. ¹H NMR (300 MHz, DMSO-d₆)δ 4.77 (d, J=7.5 Hz, 2H), 4.95 (dtd, J=24 Hz, 7.5 Hz, 1 Hz, 1H), 7.12(t, J=9 Hz, 2H), 7.23 (dd, J=9 Hz, 6 Hz, 2H), 7.49 (d, J=9 Hz, 2H), 7.50(s, 2H), 7.74 (d, J=9 Hz, 2H), 8.1 (s, 1H). MS (DCI/NH₃) m/z 422 (M+H)⁺.Anal. calc. for C₁₉H₁₄F₃N₃O₃S: C, 54.15; H, 3.34; N, 9.97. Found: C,53.88; H, 3.42; —N, 9.76.

EXAMPLE 1442-(α-Methyl-3-fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 124,substituting 3-fluoro-α-methylbenzyl chloride in place of2,4-difluorobenzyl bromide (yield: 220 mg, 65%). mp 192-194° C. ¹H NMR(300 MHz, DMSO-d₆) δ 1.76 (d, 6 Hz, 3H), 6.27 (q, J=7 Hz, 1H), 7.1 (t,J=9 Hz, 2H), 7.22 (dd, J=9 Hz, 6 Hz, 2H), 7.49 (d, J=9 Hz, 2H), 7.51 (s,2H), 7.72 (d, J=9 Hz, 2H), 8.18 (s, 1H). MS (DCI/NH₃) m/z 468 (M+H)⁺.Anal. calc. for C₂₄H₁₉F₂N₃O₃S: C, 61.66; H, 4.09; N, 8.98. Found: C,61.36; H, 3.96; N, 8.86.

EXAMPLE 1452-(1-Cyclohexenylmethyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 124,substituting 1-bromomethylcyclohexane in place of 2,4-difluorobenzylbromide (yield: 70 mg, 28%). mp 192-193° C. ¹H NMR (300 MHz, DMSO-d₆) δ1.55 (m, 4H), 1.98 (m, 4H), 4.64 (s, 2H), 5.53 (s, 1H), 7.12 (t, J=9 Hz,2H), 7.22 (dd, J=9 Hz, 6 Hz, 2H), 7.39 (d, J=9 Hz, 2H), 7.39 (s, 2H),7.72 (d, J=9 Hz, 2H), 8.07 (s, 1H). MS (DCI/NH₃) m/z 440 (M+H)⁺. Anal.calc. for C₂₃H₂₂FN₃O₃S: C, 62.85; H, 5.04; N, 9.56. Found: C, 62.47; H,5.23; N, 9.14.

EXAMPLE 1462-(α-Methyl-2,3,4-trifluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 124,substituting 2,3,4-trifluoro-α-methylbenzyl chloride in place of2,4-difluorobenzyl bromide (yield: 70 mg, 50%). mp 192-194° C. ¹H NMR(300 MHz, CDCl₃) δ 1.84 (d, J=6 Hz, 3H), 4.8 (s, 2H), 6.54 (q, J=7 Hz,1H), 6.96 (t, J=9 Hz, 2H), 6.99 (m, 1H), 7.18 (dd, J=9 Hz, 6 Hz, 2H),7.2 (m, 1H), 7.38 (d, J=9 Hz, 2H), 7.86 (d, J=9 Hz, 2H), 7.88 (s, 1H).MS (DCI/NH₃) m/z 504 (M+H)⁺. Anal. calc. for C₂₄H₁₇F₄N₃O₃S: C, 57.25; H,3.4; N, 8.34. Found: C, 56.84; H, 3.52; N, 7.91.

EXAMPLE 1472-(α-Methyl-3,5-difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 124,substituting 3,5-difluoro-α-methylbenzyl chloride in place of2,4-difluorobenzyl bromide (yield: 80 mg, 45%). mp 139-141° C. ¹H NMR(300 MHz, CDCl₃) δ 1.83 (d, J=6 Hz, 3H), 4.79 (s, 2H), 6.32 (q, J=7 Hz,1H), 6.84 (m, 1H), 6.97 (t, J=9 Hz, 2H), 7.02 (dd, J=6 Hz, 1.5 Hz, 2H),7.18 (dd, J=9 Hz, 6 Hz, 2H), 7.28 (d, J=9 Hz, 2H), 7.85 (s, 1H), 7.9 (d,J=9 Hz, 2H). MS (DCI/NH₃) m/z 486 (M+H)⁺. Anal. calc. for C₂₄H₁₈F₃N₃O₃S:C, 59.37; H, 3.73; N, 8.65. Found: C, 59.00; H, 3.70; N, 8.35.

EXAMPLE 1482-(α-Methyl-3,4-difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 124,substituting 3,4-difluoro-α-methylbenzyl chloride in place of2,4-difluorobenzyl bromide (yield: 200 mg, 58%). mp 214-215° C. ¹H NMR(300 MHz, CDCl₃) δ 1.82 (d, J=6 Hz, 3H), 4.7 (s, 2H), 6.35 (q, J=7 Hz,1H), 6.96 (t, J=9 Hz, 2H), 7.16 (m, 4H), 7.28 (d, J=9 Hz, 2H), 7.37 (m,1H), 7.84 (d, J=9 Hz, 2H), 7.90 (s, 1H). MS (DCI/NH₃) m/z 486 (M+H)⁺.Anal. calc. for C₂₄H₁₈F₃N₃O₃S: C, 59.37; H, 3.73; N, 8.65. Found: C,59.13; H, 3.73; N, 8.54.

EXAMPLE 1492-(3-Fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 124,substituting 3-fluorobenzyl bromide in place of 2,4-difluorobenzylbromide (yield: 160 mg, 61%). mp 220-222° C. ¹H NMR (300 MHz, DMSO-d₆) δ5.37 (s, 2H), 7.12 (t, J=9 Hz, 2H), 7.22 (m, 5H), 7.39 (m, 5H), 7.73 (d,J=9 Hz, 2H), 8.11 (s, 1H). MS (DCI/NH₃) m/z 454 (M+H)⁺. Anal. calc. forC₂₃H₁₇F₂N₃O₃S: C, 60.92; H, 3.77; N, 9.26. Found: C, 61.06; H, 4.22; N,8.88.

EXAMPLE 1502-(4-Fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 124,substituting 4-fluorobenzyl bromide in place of 2,4-difluorobenzylbromide (yield: 85 mg, 34%). mp 237-239° C. ¹H NMR (300 MHz, DMSO-d₆) δ5.32 (s, 2H), 7.12 (t, J=9 Hz, 2H), 7.22 (m, 4H), 7.38 (m, 4H), 7.47(dd, J=9 Hz, 6 Hz, 2H), 7.72 (d, J=9 Hz, 2H), 8.10 (s, 1H). MS (DCI/NH₃)m/z 454 (M+H)⁺. Anal. calc. for C₂₃H₁₇F₂N₃O₃S: C, 60.92; H, 3.77; N,9.26. Found: C, 60.61; H, 3.96; N, 8.74.

EXAMPLE 1512-(2,4,6-Trifluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 124,substituting 2,4,6-trifluorobenzyl bromide in place of2,4-difluorobenzyl bromide (yield: 255 mg, 73%). mp 201-203° C. ¹H NMR(300 MHz, DMSO-d₆) δ 5.38 (s, 2H), 7.13 (t, J=9 Hz, 2H), 7.23 (m, 4H),7.38 (d, J=9 Hz, 2H), 7.42 (s, 2H), 7.70 (d, J=9 Hz, 2H), 8.08 (s, 1H).MS (DCI/NH₃) m/z 490 (M+H)⁺. Anal. calc. for C₂₃H₁₅F₄N₃O₃S: C, 56.44; H,3.08; N, 8.58. Found: C, 56.31; H, 3.09; N, 8.40.

EXAMPLE 1522-(2,4,5-Trifluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 124,substituting 2,4,5-trifluorobenzyl bromide in place of2,4-difluorobenzyl bromide (yield: 180 mg, 49%). mp 236-238° C. ¹H NMR(300 MHz, DMSO-d₆) δ 5.35 (s, 2H), 7.13 (t, J=9 Hz, 2H), 7.23 (dd, J=9Hz, 6 Hz, 2H), 7.39 (d, J=9 Hz, 2H), 7.41 (s, 2H), 7.6 (m, 2H), 7.72 (d,J=9 Hz, 2H), 8.11 (s, 1H). MS (DCI/NH₃) m/z 490 (M+H)⁺. Anal. calc. forC₂₃H₁₅F₄N₃O₃S: C, 56.44; H, 3.08; N, 8.58. Found: C, 56.38; H, 3.28; N,8.41.

EXAMPLE 153 2-(2.3,4-Trifluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 124,substituting 2,3,4-trifluorobenzyl bromide in place of2,4-difluorobenzyl bromide (yield: 220 mg, 63%). mp 218-220° C. ¹H NMR(300 MHz, DMSO-d₆) δ 5.40 (s, 2H), 7.13 (t, J=9 Hz, 2H), 7.22 (dd, J=9Hz, 6 Hz, 2H), 7.34 (m, 2H), 7.39 (d, J=9 Hz, 2H), 7.42 (s, 2H), 7.73(d, J=9 Hz, 2H), 8.12 (s, 1H). MS (DCI/NH₃) m/z 490 (M+H)⁺. Anal. calc.for C₂₃H₁₅F₄N₃O₃S: C, 56.44; H, 3.08; N, 8.58. Found: C, 56.32; H, 3.24;N, 8.31.

EXAMPLE 1542-(4,4,4-Trifluoro-3-methyl-2E-butenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 124,substituting 1-bromo-3-methyl-4,4,4-trifluoro-2-butene in place of2,4-difluorobenzyl bromide (yield: 160 mg, 48%). mp 155-157° C. ¹H NMR(300 MHz, CDCl₃) δ 2.00 (s, 3H), 4.8 (s, 2H), 4.96 (d, J=7.5 Hz, 2H),6.33 (m, 1H), 6.99 (t, J=9 Hz, 2H), 7.19 (dd, J=9 Hz, 6 Hz, 2H), 7.29(d, J=9 Hz, 2H), 7.95 (s, 1H), 7.97 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z468 (M+H)⁺. Anal. calc. for C₂₁H₁₇F₄N₃O₃S: C, 53.96; H, 3.66; N, 8.98.Found: C, 53.84; H, 3.51; N, 8.77.

EXAMPLE 1552-(4-Biphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 4-bromobiphenyl in place of 4-iodo-1-fluorobenzene (yield:0.275 g, 100%). mp 249-251° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.24 (s, 3H),7.16 (m, 2H), 7.30 (m, 2H), 7.42 (m, 1H), 7.48-7.58 (m, 4H), 7.75 (m,4H), 7.84 (m, 2H), 7.91 (m, 2H), 8.27 (s, 1H). MS (DCI/NH₃) m/z 497(M+H)⁺, 514 (M+NH₄)⁺. Anal. calc. for C₂₃H₂₁FN₂O₃S: C, 70.15; H, 4.26;N, 5.64. Found: C, 69.81; H, 4.42; N, 5.41.

EXAMPLE 1562-(4-Bromophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 1,4-dibromobenzene in place of 4-iodo-1-fluorobenzene(yield: 0.337 g, 93%). ¹H NMR (300 MHz, DMSO d₆) δ 3.24 (s, 3H), 7.14(m, 2H), 7.28 (m, 2H), 7.64 (m, 2H), 7.75 (m, 2H), 7.90 (m, 2H), 8.25(s, 1H). MS (DCI/NH₃) m/z 499 (M+H)⁺, 518 (M+NH₄)⁺. Anal. calc. forC₂₃H₁₆BrFN₂O₃S.0.75H₂O: C, 53.86; H, 3.43; N, 5.46. Found: C, 53.92; H,3.16; N, 5.34.

EXAMPLE 1572-(4-Nitrophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 1-iodo-4-nitrobenzene in place of 4-iodo-1-fluorobenzene(yield: 0.45 g, 100%). mp 110-116° C. ¹H NMR (300 MHz, DMSO d₆) 83.24(s, 3H), 7.17 (m, 2H), 7.32 (m, 2H), 7.53 (m, 2H), 7.91 (m, 2H), 8.03(m, 2H), 8.34 (s, 1H), 8.40 (m, 2H). MS (DCI/NH₃) m/z 466 (M+H)⁺, 483(M+NH₄)⁺. Anal. calc. for C₂₃H₁₆FN₃O₅S: C, 59.35; H, 3.46; N, 9.03.Found: C, 59.02; H, 3.62; N, 8.82.

EXAMPLE 1582-(4-Phenoxyphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 4-bromodiphenylether in place of 4-iodo-1-fluorobenzene(yield: 0.667 g, 22%). mp 118-125° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.24(s, 3H), 7.12 (m, 5H), 7.15-7.33 (m, 4H), 7.46 (m, 2H), 7.52 (m, 2H),765 (m, 2H), 7.90 (m, 2H), 8.23 (s, 1H). MS (DCI/NH₃) m/z 513 (M+H)⁺.Anal. calc. for C₂₅H₂₁FN₂O₄S.0.75H₂O: C, 66.21; H, 4.31; N, 5.32. Found:C, 65.98; H, 4.25; N, 5.27.

EXAMPLE 1592-(4-t-Butylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 1-bromo-4-t-butyl-benzene in place of4-iodo-1-fluorobenzene. No product was observed. The solution wasconcentrated in vacuo. The resulting solid was dissolved in DMF (5 mL)and CuI (13.3 mg, 0.07 mmol) was added. The solution was allowed toreflux overnight. Upon completion, the mixture was poured into 10%citric acid and extracted with ethyl acetate. The organic layer waswashed with water, dried over MgSO₄ and concentrated in vacuo. The crudesolid was purified using flash chromatography (SiO₂), eluting with 5%diethyl ether/CH₂Cl₂ to provide the desired product (yield: 0.292 g,84%). mp 132-136° C. ¹H NMR (300 MHz, DMSO d₆) δ 1.34 (s, 9H), 3.24 (s,3H), 7.14 (m, 2H), 7.29 (m, 2H), 7.54 (m, 6H), 7.90 (m, 2H), 8.23 (s,1H). MS (DCI/NH₃) M/Z 477 (M+H)⁺, 494 (M+NH₄)⁺. Anal. calc. forC₂₇H₂₅FN₂O₃S: C, 68.05; H, 5.29; N, 5.88. Found: C, 67.94; H, 5.31; N,5.67.

EXAMPLE 1602-(4-Chlorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 4-bromo-1-chlorobenzene in place of 4-iodo-1-fluorobenzene(yield: 0.254 g, 83.5%). mp 214-216° C. ¹H NMR (300 MHz, DMSO-d₆) δ63.24(s, 3H), 7.16 (m, 2H), 7.29 (m, 2H), 7.52 (m, 2H), 7.61 (m, 2H), 7.71(m, 2H), 7.91 (m, 2H), 8.26 (s, 1H). MS (DCI/NH₃) m/z 455 (M+H)⁺, 472(M+NH₄)⁺. Anal. calc. for C₂₃H₁₆ClFN₂O₃S: C, 60.73; H, 3.55; N, 6.16.Found: C, 60.45, H, 3.41; N, 6.05.

EXAMPLE 1612-(3-Methylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 3-bromotoluene in place of 4-iodo-1-fluorobenzene (yield:0.262 g, 83%). mp 213-216° C. ¹H NMR (300 MHz, DMSO d₆) δ 2.39 (s, 3H),3.24 (s, 3H), 7.14 (m, 2H), 7.28 (m, 3H), 7.43 (m, 3H), 7.53 (m, 2H),7.80 (m, 2H), 8.22 (s, 1H). MS (DCI/NH₃) m/z 435 (M+H)⁺, 452 (M+NH₄)⁺.Anal. calc. for C₂₄H₁₉FN₂O₃S: C, 66.35; H, 4.41; N, 6.45. Found: C,66.00, H, 4.16; N, 6.23.

EXAMPLE 1622-(3-Vinylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 3-bromostyrene in place of 4-iodo-1-fluorobenzene (yield:0.202 g, 62%). mp 182-183° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.25 (s, 3H),5.35 (d, J=12 Hz, 1H), 5.92 (d, J=15 Hz, 1H), 6.82 (m, 1H), 7.15 (m,2H), 7.30 (m, 2H), 7.50-7.60 (m, 4H), 7.74 (m, 1H), 7.91 (m, 2H), 8.24(s, 1H). MS (DCI/NH₃) m/z 447 (M+H)⁺, 464 (M+NH₄)⁺. Anal. calc. forC₂₅H₁₉FN₂O₃S.0.50H₂O: C, 65.92; H, 4.42; N, 6.14. Found: C, 65.86; H,4.40; N, 6.07.

EXAMPLE 1632-(2-Formylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title was prepared according to the method of Example 62substituting 2-bromobenzaldehyde in place of 4-iodo-1-fluorobenzene(yield: 0.196 g, 60%). mp 234-236° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.24(s, 1H), 7.15 (m, 2H), 7.27 (m, 2H), 7.54 (m, 2H), 7.64-7.75 (m, 2H),7.86-7.95 (m, 3H), 8.01 (m, 1H), 8.29 (s, 1H), 10.02 (s, 1H). MS(DCI/NH₃) m/z 449 (M+H)⁺. Anal. calc. for C₂₄H₁₇FN₂O₄S.0.50H₂O: C,63.01; H, 3.96; N, 6.12. Found: 63.04; H, 3.82; N, 5.88.

EXAMPLE 1642-(2-Nitrophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 1-bromo-2-nitrobenzene in place of 4-iodo-1-fluorobenzene(yield: 0.307 g, 90.8%). mp 236-239° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.24(s, 3H), 7.12-7.27 (m, 4H), 7.56 (m, 2H), 7.7-8.01 (m, 5H), 8.18 (m,1H), 8.35 (s, 1H). MS (DCI/NH₃) m/z 466 (M+H)⁺, 483 (M+NH₄)⁺. Anal.calc. for C₂₃H₁₆FN₃O₅S.0.25H₂O: C, 58.78; H, 3.53; N, 8.94. Found: C,58.63; H, 3.54; N, 8.88.

EXAMPLE 1652-(3-Chlorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)Phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 1-bromo-3-chlorobenzene in place of 4-iodo-1-fluorobenzene(yield: 0.255 g, 77%). mp 232-235° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.23(s, 3H), 7.14 (m, 2H), 7.29 (m, 2H), 7.49-7.58 (m, 4H), 7.66 (m, 1H),7.79 (m, 1H), 7.90 (m, 2H), 8.25 (s, 1H). MS (DCI/NH₃) m/z 455 (M+H)⁺,472 (M+NH₄)⁺. Anal. calc. for C₂₃H₁₆ClFN₂O₃S: C, 60.73; H, 3.55; N,6.16. Found: C, 60.40; H, 3.43; N, 5.98.

EXAMPLE 1662-(3-Bromophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 1,3 dibromobenzene in place of 4-iodo-1-fluorobenzene(yield: 0.216 g, 60%). mp 210-212° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.23(s, 3H), 7.15 (m, 2H), 7.29 (m, 2H), 7.48-7.55 (m, 3H), 7.69 (m, 2H),7.90 (m, 3H), 8.26 (s, 1H). MS (DCI/NH₃) m/z 499 (M+H)⁺, 519 (M+H)⁺.Anal. calc. for C₂₃H₁₆BrFN₂O₃S: C, 55.32; H, 3.23; N, 5.61. Found: C,55.12; H, 3.12; N, 5.51.

EXAMPLE 1672-(4-Cyanophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 4-bromobenzonitrile in place of 4-iodo-1-fluorobenzene(yield: 0.349 g, 100%). mp 273-278° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.24(s, 3H), 7.11-7.21 (m, 2H), 7.25-7.35 (m, 2H), 7.52 (m, 2H), 7.88-7.96(m, 4H), 8.04 (m, 2H), 8.31 (s, 1H). MS (DCI/NH₃) m/z 445 (M+H)⁺. Anal.calc. for C₂₄H₁₆FN₃O₃S: C, 64.71; H, 3.62; N, 9.43. Found: C, 64.50; H,3.53; N, 9.35.

EXAMPLE 1682-(5-Methyl-2-thienyl))-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 2-bromo-5-methylthiophene in place of4-iodo-1-fluorobenzene (yield: 0.200 g, 62%). mp 219-224° C. ¹H NMR (300MHz, DMSO d₆) δ 2.45 (s, 3H), 3.23 (s, 3H), 6.80 (m, 1H), 7.17 (m, 2H),7.29 (m, 2H), 7.52 (m, 3H), 7.89 (m, 2H), 8.33 (s, 1H). MS (DCI/NH₃) m/z441 (M+H)⁺, 458 (M+NH₄)⁺. Anal. calc. for C₂₂H₁₇FN₂O₃S₂: C, 59.99; H,3.89; N, 6.36. Found: C, 59.90; H, 3.91; N, 6.26.

EXAMPLE 1692-(3-Biphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 3-bromobiphenyl in place of 4-iodo-1-fluorobenzene (yield:0.28 g, 78%). mp 126-134° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.24 (s, 3H),7.15 (m, 2H), 7.31 (m, 2H), 7.37-7.45 (m, 1H), 7.51 (m, 4H), 7.64 (m,2H), 7.68-7.79 (m, 3H), 7.92 (m, 3H), 8.27 (s, 1H). MS (DCI/NH₃) m/z 497(M+H)⁺, 514 (M+NH₄)⁺. Anal. calc. for C₂₉H₂₁FN₂O₃S: C, 70.15; H, 4.26;N, 5.64. Found: C, 69.91; H, 4.33; N, 5.74.

EXAMPLE 1702-(3,5-Dimethylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 5-bromo-m-xylene in place of 4-iodo-1-fluorobenzene (yield:0.152 g, 46.5%). mp 130-134° C. ¹H NMR (300 MHz, DMSO d₆) δ 2.34 (s,6H), 3.23 (s, 3H), 7.07-7.12 (m, 2H), 7.15 (m, 1H), 7.21-7.32 (m, 4H),7.52 (m, 2H), 7.90 (m, 2H), 8.29 (s, 1H). MS (DCI/NH₃) m/z 449 (M+H)⁺,466 (M+NH₄)⁺. Anal. calc; for C₂₅H₂₁FN₂O₃S: C, 66.95; H, 4.72; N, 6.25.Found: C, 66.81; H, 4.57; N, 6.07.

EXAMPLE 1712-(3,4-Difluorophenyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

4-(4-Fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonewas prepared according to the method of Example 11, starting with2-benzyl-4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 0.3319 g, 83%).

The title compound was prepared according to the method of Example 62substituting4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone andsubstituting 1-bromo-3,4-difluorobenzene in place of4-iodo-1-fluorobenzene (yield: 0.085 g, 54%). mp 157-159° C. ¹H NMR (300MHz, DMSO d₆) δ 3.30 (s, 3H), 3.88 (bs, 2H), 7.04 (m, 4H), 7.49-7.66 (m,2H), 7.70 (m, 2H), 7.81 (m, 1H), 8.12 (s, 1H). MS (DCI/NH₃) m/z 471(M+H)⁺, 488 (M+NH₄)⁺. Anal. calc. for C₂₄H₁₇F₃N₂O₃S.0.25H₂O: C, 60.69;H, 3.71; N, 5.84. Found: C, 6.39; H, 3.76; N, 5.81.

EXAMPLE 1722-(3-Chloro-4-fluorophenyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone andsubstituting 4-bromo-2-chloro-1-fluorobenzene in place of4-iodo-1-fluorobenzene (yield: 0.110 g, 74%). mp 153-156° C. ¹H NMR (300MHz, DMSO d₆) δ 3.30 (s, 3H), 3.89 (bs, 2H), 7.02-7.07 (m, 4H), 7.59 (m,1H), 7.65-7.72 (m, 4H), 8.07 (m, 2H), 8.12 (s, 1H). MS (DCI/NH₃) m/z 487(M+H)⁺, 504 (M+NH₄)⁺. Anal. calc. for C₂₄H₁₇ClF₂N₂O₃S.0.25H₂O: C, 58.65;H, 3.58; N, 5.64. Found: C, 58.41; H, 3.56; N, 5.36.

EXAMPLE 1732-(2-Thienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 2-bromothiophene in place of 1-bromo-4-fluorobenzene(yield: 98 mg, 40%). mp 215-217° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.25 (s,3H), 7.18 (m, J=9 Hz, 3H), 7.29 (m, 2H), 7.42 (d, 2H), 7.75 (d, 1H),7.93 (d, J=9 Hz), 8.4 (s, 1H). MS (DCI/NH₃) m/z 427 (M+H)⁺, 444(M+NH₄)⁺. Anal. calc. for C₂₁H₁₅FN₂O₃S₂: C, 59.14; H, 3.54; N, 6.57.

EXAMPLE 1742-(4-Trifluoromethylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 1-bromo-4-trifluoromethylbenzene in place of1-bromo-4-fluorobenzene (yield: 185 mg, 64%). mp 171-173° C. ¹H NMR (300MHz, DMSO-d₆) δ 3.25 (s, 3H), 7.18 (t, 2H), 7.29 (m, 2H), 7.52 (d, J=9Hz 2H), 7.91 (d, J=9 Hz, 2H), 7.93 (s, 4H), 8.32 (s, 1H). MS (DCI/NH₃)m/z 489 (M+H)⁺, 506 (M+NH₄)⁺. Anal. calc. for C₂₄H₁₆F₄N₂O₃S: C, 59.02;H, 3.3; N, 5.74. Found: C, 58.75; H, 3.35; N, 5.69.

EXAMPLE 1752-[4-(1-Pyrroyl)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 1-(4-iodophenyl)pyrrole in place of 1-bromo-4-fluorobenzene(yield: 140 mg, 50%). mp 229-231° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.25(s, 3H), 6.3 (t, 2H), 7.18 (t, 2H), 7.29 (m, 2H), 7.46 (t, 2H) 7.53 (d,J=9 Hz 2H), 7.75 (s, 4H), 7.91 (d, J=9 Hz, 2H), 8.27 (s, 1H). MS(DCI/NH₃) m/z 486 (M+H)⁺, 504 (M+NH₄)⁺. Anal. calc. forC₂₇H₂₀FN₃O₃S.0.5H₂O: C, 66.79; H, 4.15; N, 8.65. Found: C, 65.21; H,4.29; N, 8.12.

EXAMPLE 1762-(5-Chloro-2-thienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 2-bromo-5-chlorothiophene in place of1-bromo-4-fluorobenzene (yield: 225 mg, 93%). mp 190-192° C. ¹H NMR (300MHz, DMSO-d₆) δ 2.38 (s, 3H), δ 3.25 (s, 3H), 7.15 (t, 2H), 7.29 (m,4H), 7.5 (D, 4H) 7.91 (d, J=9 Hz, 2H), 8.21 (s, 1H). MS (DCI/NH₃) m/z435 (M+H), 452 (M+NH₄)⁺. Anal. calc. for C₂₄H₁₉F N₂O₃S: C, 66.35; H,4.41; N, 6.45. Found: C, 66.15; H, 4.37; N, 6.3.

EXAMPLE 1772-(4-Methylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 1-bromo-4-methylbenzene in place of 1-bromo-4-fluorobenzene(yield: 79 mg, 31%). mp 190-192° C. ¹H NMR (300 MHz, DMSO-d₆) δ 2.38 (s,3H), δ 3.25 (s, 3H), 7.15 (t, 2H), 7.29 (m, 4H), 7.5 (D, 4H) 7.91 (d,J=9 Hz, 2H), 8.21 (s, 1H). MS (DCI/NH₃) m/z 435 (M+H)⁺, 452 (M+NH₄)⁺.Anal. calc. for C₂₄H₁₉F N₂O₃S: C, 66.35; H, 4.41; N, 6.45. Found: C,66.15; H, 4.37; N, 6.3.

EXAMPLE 1782-(4-Fluorophenyl)-4-(2-ethyl-1-hexyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

To a solution of 2-ethyl-1-hexanol (65 mg, 0.5 mmol) in THF (15 mL) atroom temperature was added NaH (60% oil suspension) (20 mg, 0.5 mmol)and after 10 minutes2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(193 mg, 0.5 mmol) was added. The resulting mixture was stirred at roomtemperature for the next 2 hours. The mixture was quenched with 10%citric acid and extracted with ethyl acetate. The extract was washedwith water, brine, dried with MgSO₄, and purified by chromatography(silica gel, 2:1 hexanes-ethyl acetate) to provide the desired product(yield: 140 mg, 60%). mp 120-122° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.75(m, 6H), 1.1 (m, 6H), 1.20 (quintet, J=7 Hz, 2H), 1.44 (m, 1H), 3.27 (s,3H), 4.30 (d, J=6 Hz, 2H), 7.37 (t, J=9 Hz, 2H), 7.65 (m, 2H), 7.89 (d,J=9 Hz, 2H), 8.06 (d, J=9 Hz, 2H), 8.18 (s, 1H). MS (APCI+) m/z 473(M+H)⁺; (APCI−) m/z 507 (M+Cl)⁻. Anal. calc. for C₂₅H₂₉FN₂O₄S.0.5H₂O: C,62.35; H, 6.27; N, 5.87. Found: C, 62.22; H, 6.14; N, 6.22.

EXAMPLE 1792-(3-Thienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 3-bromothiophene in place of 1-bromo-4-fluorobenzene(yield: 225 mg, 93%). mp 200-202° C. ¹H NMR (390 MHz, DMSO-d₆) δ 3.25(s, 3H), 7.15 (t, 2H), 7.29 (m, 0.2H), 7.5 (d, J=9 Hz, 2H), 7.6 (M, 1H)7.66 (dd, 1H), 7.91 (d, J=9 Hz, 2H), 8.13 (dd, 1H), 8.25 (s, 1H). MS(DCI/NH₃) m/z 427 (M+H)⁺, 444 (M+NH₄)⁺. Anal. calc. for C₂₁H₁₅FN₂O₃S₂:C, 55.07; H, 4.07; N, 6.11. Found: C, 54.63; H, 3.47; N, 6.01.

EXAMPLE 1802-(3,5-Difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 3,5-difluorobromobenzene in place of1-bromo-4-fluorobenzene (yield: 250 mg, 96%). mp 166-168° C. ¹H NMR (300MHz, DMSO-d₆) δ 3.25 (s, 3H), δ 7.15 (t, 2H), 7.27 (m, 2H), 7.4 (m, 1H),7.41 (m, 2H), 7.51 (d, J=9 Hz, 4H), 7.9 (d, J=9 Hz, 2H), 8.3 (s, 1H). MS(DCI/NH₃) m/z 457 (M+H)⁺, 474 (M+NH₄)⁺. Anal. calc. for C₂₃H₁₅F₃N₂O₃S:C, 60.13; H, 3.31; N, 6.14. Found: C, 60.49; H, 3.31; N, 6.03.

EXAMPLE 1812-(2,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 2,4-difluorobromobenzene in place of1-bromo-4-fluorobenzene (yield: 40 mg, 15%). mp 245-247° C. ¹H NMR (300MHz, DMSO-d₆) δ 3.23 (s, 3H), δ 7.15 (t, 2H), 7.3 (t, 2H), 7.54 (m, 2H),7.57 (m, 2H), 7.75 (m, 1H), 7.9 (d, J=9 Hz, 2H), 8.27 (s, 1H). MS(DCI/NH₃) m/z 457 (M+H)⁺, 474 (M+NH₄)⁺. Anal. calc. for C₂₈H₁₅F₃N₂O₃S:C, 60.52; H, 3.31; N, 6.03.

EXAMPLE 1822-(3,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 3,4-difluorobromobenzene in place of1-bromo-4-fluorobenzene (yield: 170 mg, 70%). mp 109-110° C. ¹H NMR (300MHz, DMSO-d₆) δ 3.23 (s, 3H), δ 7.15 (t, 2H), 7.3 (t, 2H), 7.25 (m, 2H),7.59 (m, 4H), 7.83 (m, 1H), 7.9 (d, J=9 Hz, 2H), 8.27 (s, 1H). MS(DCI/NH₃) m/z 457 (M+H)⁺, 474 (M+NH₄)⁺. Anal. calc. for C₂₃H₁₅F₃N₃O₃S:C, 60.52; H, 3.31; N, 6.14. Found 60.60; H, 3.48; N, 5.89

EXAMPLE 1832-(3-Furyl)-4-(4-fluoro-phenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 3-bromofuran in place of 1-bromo-4-fluorobenzene (yield:175 mg, 73%). mp 239-242° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.25 (s, 3H),7.09 (d, 1H), 7.15 (t, 2H), 7.29 (m, 2H), 7.5 (d, J=9 Hz 2H), 7.8 (t,1H) 7.91 (d, J=9 Hz, 2H), 8.3 (s, 1H), 8.58 (s, 1H). MS (DCI/NH₃) m/z411 (M+H)⁺, 428 (M+NH₄)⁺. Anal. calc. for C₂₁H₁₅F N₂O₄S.0.5H₂O: C,61.46; H, 3.68; N, 6.83. Found: C, 59.91; H, 3.54; N, 6.54.

EXAMPLE 1842-(3-Fluoro-4-methoxyphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 3-fluoro-4-methoxybromobenzene in place of1-bromo-4-fluorobenzene (yield: 230 mg, 85%). mp 97-101° C. ¹H NMR (300MHz, DMSO-d₆) δ 3.25 (s, 3H), 3.9 (s, 3H), 7.16 (d, 1H), 7.29 (m, 3H),7.5 (m, 4H), 7.91 (d, J=9 Hz, 2H), 8.23 (s, 1H). MS (DCI/NH₃) m/z 469(M+H)⁺, 491 (M+NH₄)⁺. Anal. calc. for C₂₄H₁₈F₂N₂O₄S.0.5H₂O: C, 61.53; H,3.87; N, 5.98. Found: C, 61.18; H, 4.01; N, 5.58.

EXAMPLE 1852-(2-Fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 2-fluorobromobenzene in place of 1-bromo-4-fluorobenzene(yield: 195 mg, 75%). mp 96-103° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.23 (s,3H), δ 7.15 (t, 2H), 7.3 (m, 3H), 7.55 (m, 5H), 7.9 (d, J=9 Hz, 2H),8.27 (s, 1H). MS (ESI) m/z 437 (M−H)⁺). Anal. calc. for C₂₃H₁₆F₂N₂O₃S:C, 63.01; H, 3.68; N, 6.39. Found, C, 62.91; H, 4.06; N, 5.99.

EXAMPLE 1862-[4-(Aminosulfonyl)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 4-aminosulfonyl-1-bromobenzene in place of1-bromo-4-fluorobenzene. mp 213-216° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.25(s, 3H), 7.15 (t, 2H), 7.29 (m, 2H), 7.53 (s, 2H) 7.55 (s, 1H), 7.7 (dd,2H) 7.91 (t, 4H), 7.98 (d, 2H), 8.3 (s, 1H). MS (DCI/NH₃) m/z 499(M+H)⁺, 517 (M+NH₄)⁺. Anal. calc. for C₂₃H₁₈FN₃O₅S₂.0.5H₂O: C, 55.30; H,3.63; N, 8.41. Found: C, 54.4; H, 3.79; N, 7.78.

EXAMPLE 1872-(3-Chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 3-chloro-4-fluoro-1-bromobenzene in place of1-bromo-4-fluorobenzene (yield: 320 mg, 78%). mp 155-157° C. ¹H NMR (300MHz, DMSO-d₆) δ 3.23 (s, 3H), δ 7.15 (t, 2H), 7.3 (t, 2H), 7.25 (m, 2H),7.53 (d, J=9 Hz, 2H), 7.59 (t, 1H), 7.73 (m, 1H), 7.9 (d, J=9 Hz, 2H)7.96 (m, 1H), 8.27 (s, 1H). MS (DCI/NH₃) m/z 473 (M+H)⁺, 490 (M+NH₄)⁺.Anal. calc. for C₂₃H₁₅ClF₂N₂O₃S: C, 5.8.42; H, 3.2; N, 5.92. Found58.23; H, 2.87; N, 5.70

EXAMPLE 1882-(3,5-Dichlorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 3,5-dichlorobenzene in place of 1-bromo-4-fluorobenzene(yield: 360 mg, 78%). mp 289-294° C. ¹H NMR (300 MHz, DMSO-d) δ 3.25 (s,3H), δ 7.15 (t, 2H), 7.27 (m, 2H), 7.51 (d, J=9 Hz, 4H), 7.75 (t, 1H),7.83 (d, 2H), 7.9 (d, J=9 Hz, 2H), 8.3 (s, 1H). MS (DCI/NH₃) m/z 490(M+H)⁺, 507 (M+NH₄)⁺. Anal. calc. for C₂₃H₁₅Cl₂FN₂O₃S.0.5H₂O: C, 56.45;H, 3.09; N, 5.72. Found: C, 55.36; H, 3.00; N, 5.50.

EXAMPLE 1892-(4-Fluoro-3-methylphenyl-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 1-bromo-4-fluoro-3-methylbenzene in place of1-bromo-4-fluorobenzene (yield: 275 mg, 71%). mp 168-170° C. ¹H NMR (300MHz, DMSO-d₆) δ 2.3 (s, 3H), δ 3.25 (s, 3H), 7.15 (t, 2H), 7.3 (m, 3H),7.56 (m, 4H), 7.9 (d, 2H), 8.23 (s, 2H). MS (DCI/NH₃) m/z 453 (M+H), 471(M+NH₄)⁺. Anal. calc. for C₂₄H₁₈F₂N₂O₃S: C, 63.71; H, 4.01; N, 6.01.Found: C, 63.53; H, 4.06; N, 5.92.

EXAMPLE 1902-(4-Chloro-3-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 4-bromo-1-chloro-2-fluorobenzene in place of1-bromo-4-fluorobenzene (yield: 220 mg, 80%). mp 102-110° C. ¹H NMR (300MHz, DMSO-d₆) δ 3.23 (s, 3H), 7.11-7.19 (m, 2H), 7.25-7.32 (m, 2H), 7.51(d, J=5.6 Hz, 2H), 7.58-70.64 (m, 1H), 7.75-7.87 (m, 2H), 7.91 (d, J=5.6Hz, 2H), 8.28 (s, 1H). MS (APCI+) m/z 473 (M+H)⁺.

EXAMPLE 1912-(4-Chloro-2-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62substituting 1-bromo-4-chloro-2-fluorobenzene in place of1-bromo-4-fluorobenzene (yield: 65 mg 24%). mp 250-260° C. ¹H NMR (300MHz, DMSO-d₆) δ 3.21 (s, 3H), 7.12-7.19 (m, 2H), 7.25-7.32 (m, 2H),7.49-7.58 (m, 3H), 7.68-7.78 (m, 2H), 7.91 (d, J=8.7 Hz, 2H), 8.29 (s,1H). MS (APCI+) m/z 473 (M+H)⁺. Anal. calc. for C₂₃H₁₅ClF₂N₂O₃S: C,58.41; H, 3.19; N, 5.92. Found: C, 58.69; H, 3.45; N, 5.78.

EXAMPLE 1922-(1-Adamantyloxycarbonyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A solution of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone,prepared according to the procedure of Example 11 (200 mg, 0.58 mmol) inCH₂Cl₂ (8 ml) was prepared and stirred. 1-Adamantylfluoroformate (172mg, 0.87 mmol), dimethylaminopyridine (14 mg, 0.011 mmol) andtriethylamine (0.12 ml, 0.87 mmol) were added. The reaction mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith CH₂Cl₂ (50 ml) and washed with 10% citric acid (50 ml), brine (50ml) and dried over MgSO₄, and concentrated in vacuo. The resulting cruderesidue was purified using flash chromatography (SiO₂, eluting with 15:1CH₂Cl₂:diethyl ether) to provide the desired product (yield: 55 mg,18%). ¹H NMR (300 MHz, DMSO-d₆) δ 1.66 (bs, 6H), 2.25 (bd, 10H), 3.21(s, 3H), 7.15 (t, 2H), 7.24 (m, 2H), 7.6 (dd, 2H), 7.88 (d, J=9 Hz, 2H),8.15 (s, 1H). MS (ESI) m/z 521 (M−H)⁺. Anal. calc. for C₂₁H₁₅F N₂O₃S₂:C, 64.35; H, 5.20; N, 5.36.

EXAMPLE 1932-(2,2,2-Trifluoroethyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 193A 2-(2,2,2-Trifluoroethyl)-4,5-dichloro-3(2H)-pyridazinone

2,2,2-Trifluoroethylhydrazine (70% solution in water, 35.0 g, 0.307 mol)was treated with mucochloric acid (51.88 g, 0.307 mol) in ethanol (300mL) and refluxed for 5 hours. The solvent was concentrated in vacuo. Thecrystals obtained were washed with water and air dried (yield: 50 g;67.5%). ¹H NMR (300 MHz, CDCl₃) δ 4.8 (q, J=9 Hz, 2H), 7.85 (s, 1H). MS(DCl—NH₃) m/z 264 (M+NH₄)⁺.

EXAMPLE 193B2-(2,2,2-Trifluoroethyl)-4-chloro-5-hydroxy-3(2H)-pyridazinone

2-(2,2,2-Trifluoroethyl)-4,5-dichloro-3(2H)-pyridazinone (15.0 m 60.7mmol), and potassium carbonate (10 g, 72.4 mmol.) were mixed with water(500 mL) and stirred at reflux for 6 hours. TLC (1:1:2CH₂Cl₂/hexanes/ethyl acetate) indicated that all starting material wasconsumed.) The reaction mixture was cooled to room temperature. The pHof the reaction mixture was adjusted to about 4 with hydrochloric acid(15%). The product was extracted with ethyl acetate (700 mL). Theorganic phase was washed with brine, dried over anhydrous MgSO₄ andfiltered. The filtrate was concentrated under reduced pressure. Thehydroxy compound was obtained as a light brown solid (yield: 13.1 g,94%). ¹H NMR (300 MHz, DMSO-d₆) δ 4.92 (q, J=9 Hz, 2H), 7.9 (s, 1H). MS(DCI/NH₃) m/z 229 (M+H)⁺.

EXAMPLE 193C2-(2,2,2-Trifluoroethyl)-4-chloro-5-(trifluoromethylsulfonyloxy)-3(2H)-pyridazinone

Anhydrous Na₂CO₃ (9.04 m, 85.32 mmol) was placed in a 500 mL roundbottom flask and anhydrous CH₂CL₂ (200 mL) was added. The reactionmixture was cooled to 0° C. under N₂. The halohydroxy pyridazinoneprepared in Example 193B was dissolved in CH₂CL₂ (100 mL) and addedslowly to the flask and stirred overnight. The reaction slowly warmed toroom temperature. (TLC (2:1 hexanes/ethyl acetate) indicated completionof the reaction.) The reaction was quenched with H₂O. The organic phasecontaining the product was separated, washed with brine and dried overMgSO₄. The resulting filtrate was concentrated under reduced pressure.The crude product was isolated as deep red-brown residue. Purificationusing a silica gel column (30:70 ethyl acetate/pentanes) provided thetitle compound as a dark, reddish residue (14.3 m, 70%). ¹H NMR (300MHz, CDCl₃) δ 4.85 (q, J=9 Hz, 2H), 7.9 (s, 1H). MS (DCI/NH₃) m/z 378(M+NH₄)⁺.

EXAMPLE 193D2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

A solution of the triflate prepared in Example 193C (1.56 g 4.3 mmol),4-(methylthio)phenylboronic acid (870 mg, 5.16 mmol),tetrakis(triphenylphosphine)palladium(0) (250 mg, 5% mmol) andtriethylamine (1.44 ml, 10.32 mmol) in toluene was heated at reflux for1 hour. The mixture was partitioned between ethyl acetate and water. Theethyl acetate layer was washed with water, then brine, followed bydrying over MgSO₄ and filtration. The filtrate was concentrated invacuo. The residue was purified by column chromatography (silica gel,92:8 hexanes/ethyl acetate) to provide the coupled intermediate as apale, greenish-yellow solid (yield: 500 mg, 35%). mp 130-139° C. ¹H NMR(300 MHz, CDCl₃) δ 2.55 (s, 3H), 4.87 (q, J=9 Hz, 2H), 7.37 (d, J=9 Hz,2H), 7.48 (d, J=9 Hz, 2H), 7.82 (s, 1H). MS (DCI/NH₃) m/z 335 (M+H)⁺.

EXAMPLE 193E2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 10,substituting the coupled intermediate prepared in Example 193D in placeof2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(yield: 440 mg, 81%). mp 221-222° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.33(s, 3H), 5.10 (q, J=9 Hz, 2H), 7.90 (d, J=9 Hz, 2H), 8.12 (d, J=9 Hz,2H), 8.20 (s, 1H). MS (DCI/NH₃) m/z 367 (M+H)⁺. X1E AH

EXAMPLE 193F2-(2,2,2-Trifluoroethyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

Magnesium turnings (500 mg) were placed in a dry 250 mL round bottomflask. Anhydrous ether (20 mL) was added under N₂ at room temperaturethen fluorobenzyl bromide (3 mL) was added and stirred. The reaction washeated at 40° C. for 2 hours. All magnesium was consumed resulting in apale brownish-yellow solution. The2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneprepared in Example 193E was dissolved in dry THF (25 mL) andtransferred to the Grignard solution. The mixture was heated for 3hours. TLC (2:1 hexanes/ethyl acetate) indicated that the pyridazinonestarting material was consumed.) The reaction was cooled to roomtemperature then quenched with a saturated NH₄Cl solution. The productwas extracted with ethyl acetate (250 mL); and the organic layer waswashed with saturated NH₄Cl, and brine. The ethyl acetate solution wasdried over MgSO₄ and filtered. The filtrate was concentrated underreduced pressure. The product was isolated as an orange residue.Purification using a silica gel column (20:80 ethyl acetate/pentanes)provided the title compound as a pale yellow powder (yield: 140 mg,28%). ¹H NMR (300 MHz, CDCl₃) δ 3.13 (s, 3H), 4.85 (m, 2H), 6.93 (m,4H), 7.49 (d, J=9 Hz, 2H) 7.72 (s, 1H), 8.08 (d, J=9 Hz, 2H). MS(DCI/NH₃) m/z 441 (M+H)⁺. Anal. calc. for C₂₀H₁₆F₄N₂O₃S.0.5 H₂O: C,53.45; H, 3.81; N, 6.23. Found C, 53.45; H, 3.81; N, 6.23.

EXAMPLE 1942-(4-Fluorophenyl)-4-(4-fluorophenoxymethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 194A 2-(4-Fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone

Mucobromic acid (5.0 g, 19.4 mmol) dissolved in acetic acid (110 mL) wastreated with 4-fluorophenyl hydrazine. HCl, and the heterogeneousmixture brought to reflux at a bath temperature of 115° C. for 15 hours.During the course of reaction, the mixture became a homogeneous deep redsolution, and upon cooling to 23° C., a crystalline precipitate formed.The solution was poured into ice water (1000 mL) and stirred for 20minutes. The yellow/brown crystals were filtered off, washed withadditional cold water, and dried in vacuo to provide 5.8 g (86%) ofproduct. (J. Het. Chem., 1993, 30, 1501; Heterocycles 1985, 23, 2603) ¹HNMR (300 MHz, DMSO-d₆) δ 7.31-7.41 (m, 2H), 7.57-7.64 (m, 2H), 8.29 (s,1H). MS (DCI+) m/z 347 (Br₇₉Br₇₉ M+H)⁺, m/z 349 (Br₇₉Br₈₁ M+H)⁺, m/z 364(Br₇₉Br₇₉ M+NH₄)⁺, and m/z 366 (Br₇₉Br₈₁ M+NH₄)⁺.

EXAMPLE 194B 2-(4-Fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone

A 23° C. homogeneous solution of2-(4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone (7.18 g, 20.6 mmol)prepared above in tetrahydrofuran (322 mL) was treated with methanol(0.843 mL, 20.8 mmol) and after 5 minutes with NaH (0.833 g, 20.8 mmol,60% oil dispersion). The reaction exothermed for several minutes andthen was continued for 8 hours at 23° C. (Note: several reactions haverun to completion at this point). The reaction did not run tocompletion, and so the temperature was raised to reflux for 4 hoursmore. The reaction was still not completed. An additional 0.1 equivalentof NaOMe solution was prepared in a separate flask as above with thequantities: 32 mL of tetrahydrofuran, 0.084 mL of methanol, and 83 mg of60% NaH oil dispersion. This NaOMe solution was added via syringe to thereaction mixture cooled to 23° C., and then the temperature raised toreflux for 4 hours The reaction was still not complete, and so another0.1 equivalent NaOMe solution was prepared, added, and the reactionbrought to reflux, as above. After this 4 hours, the reaction wascompleted. The mixture was cooled to 23° C. and diluted to 2000 mL withwater. The yellow/white precipitate that formed was filtered off, washedwith additional water, and concentrated in vacuo to provide 5.39 g (88%)of product. (J. Het. Chem., 1988, 25, 1757) ¹H NMR (300 MHz, DMSO-d₆) δ4.13 (s, 3H), 7.30-7.40 (m, 2H), 7.56-7.62 (m, 2H), 8.22 (s, 1H). MS(APCI+) m/z 299 (⁷⁹Br M+H)⁺ and m/z 301 (⁸¹Br M+H)⁺.

EXAMPLE 194C2-(4-Fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 6starting with 2-(4-fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone inplace of 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone and substituting4-(methylthio)benzeneboronic acid in place of4-fluorobenzeneboronic-acid (yield: 70 mg, 61%). ¹H NMR (500 MHz,DMSO-d₆) δ 2.54 (s, 3H), 4.02 (s, 3H), 7.35 (dd, J=9.0, 9.0 Hz, 2H),7.39 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.65 (dd, J=9.0, 5.0 Hz,2H), 8.14 (s, 1H). MS (APCI+) m/z 343 (M+H)⁺.

EXAMPLE 194D2-(4-Fluorophenyl)-4-methyl-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228substituting methyl magnesium bromide in place of cyclohexylmagnesiumchloride (yield: 0.83 g, 87%). ¹H NMR (300 MHz, CDCl₃) δ 2.25 (s, 3H),2.55 (s, 3H), 7.17 (dd, J=8.8, 8.8 Hz, 2H), 7.31 (d, J=8.7 Hz, 2H), 7.38(d, J=8.7 Hz, 2H), 7.61-7.68 (m, 2H), 7.82 (s, 1H). MS (APCI+) m/z 327(M+H)⁺.

EXAMPLE 194E2-(4-Fluorophenyl)-4-methyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 10substituting2-(4-fluorophenyl)-4-methyl-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonein place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(yield: 473 mg, 86%). ¹H NMR (300 MHz, CDCl₃) δ 2.24 (s, 3H), 3.14 (s,3H), 7.19 (dd, J=8.8, 8.8 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.63-7.69 (m,2H), 7.80 (s, 1H), 8.12 (d, J=8.4 Hz, 2H). MS (APCI+) m/z 359 (M+H)⁺ andm/z 376 (M+NH₄)⁺.

EXAMPLE 194F2-(4-Fluorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

To a heterogeneous, refluxing solution of2-(4-fluorophenyl)-4-methyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(590 mg, 1.65 mmol) and carbon tetrachloride (24 mL) was quickly addedN-bromosuccinimide (yield: 308 mg, 1.73 mmol) followed by benzoylperoxide (12 mg, 0.05 mmol). After 1 hour the reaction had only run tonear 50% completion. Additional benzoyl peroxide (12 mg, 0.05 mmol) wasadded, and the reaction checked after another 1 hour. The reaction wasstill not complete, and so more benzoyl peroxide (4 mg, 0.017 mmol) wasadded. After 30 minutes, the reaction was completed. The mixture wascooled to 23° C. and diluted with ethyl acetate. The acetate solutionwas washed with saturated NaHCO₃, water, and brine. The solution wasdried over MgSO₄, filtered, and concentrated in vacuo. The residue waschromatographed (flash silica gel, ethyl acetate/hexanes gradient 1:1 to4:1) to provide the product (yield: 530 mg, 74%). ¹H NMR (300 MHz,CDCl₃) δ 3.16 (s, 3H), 4.34 (s, 2H), 7.20 (dd, J=8.8, 8.8 Hz, 2H),7.67-7.74 (m, 2H), 7.82 (d, J=8.7 Hz, 2H), 7.86 (s, 1H), 8.17 (d, J=8.7Hz, 2H). MS (APCI+) m/z 437 (M+H)⁺.

EXAMPLE 194G2-(4-Fluorophenyl)-4-(4-fluorophenoxymethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

To a homogeneous solution of2-(4-fluorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone,Example 194F, (107 mg, 0.246 mmol) and 4-fluorophenol (30.3 mg, 0.270mmol) dissolved in acetone (4 mL) was added powdered K₂CO₃ (37.3 mg,0.270 mmol). The mixture was stirred at 23° C. for 2 hours, filteredthrough a bed of Celite®, and concentrated in vacuo. The residue waschromatographed (flash silica gel, ethyl acetate/hexanes 3:2) to providethe product (yield: 83 mg, 72%). mp 65-80° C. ¹H NMR (300 MHz, CDCl₃) δ3.12 (s, 3H), 4.94 (s, 2H), 6.78-6.86 (m, 2H), 6.91-7.00 (m, 2H),7.15-7.24 (m, 2H), 7.65-7.72 (m, 2H), 7.74 (d, J=8.7 Hz, 2H), 7.93 (s,1H), 8.08 (d, J=8.7 Hz, 2H). MS (APCI+) m/z 469 (M+H)⁺. Anal. calc. forC₂₄H₁₈F₂N₂O₄S: C, 61.53; H, 3.87; N, 5.97. Found: C, 61.22; H, 3.63; N,5.64.

EXAMPLE 1952-(4-Fluorophenyl)-4-(3-fluorophenoxymethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 194Gsubstituting 3-fluorophenol in place of 4-fluorophenol (yield: 94 mg,88%). mp 142-144° C. ¹H NMR (300 MHz, CDCl₃) δ 3.12 (s, 3H), 4.98 (s,2H), 6.49-6.56 (m, 1H), 6.60-6.73 (m, 2H), 7.15-7.25 (m, 3H), 7.65-70.75(m, 4H), 7.93 (s, 1H), 8.07 (d, J=8.7 Hz, 2H). MS (APCI+) m/z 469(M+H)⁺. Anal. calc. for C₂₄H₁₈F₂N₂O₄S: C, 61.53; H, 3.87; N, 5.97.Found: C, 61.20; H, 3.92; N, 5.86.

EXAMPLE 1962-(4-Fluorophenyl)-4-phenoxymethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 294Gsubstituting phenol in place of 4-fluorophenol (yield: 67 g, 93%). mp42-75° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.28 (s, 3H), 4.92 (s, 2H),6.83-6.90 (m, 2H), 6.91-6.99 (m, 1H), 7.22-7.30 (m, 2H), 7.35-7.44 (m,2H), 7.66-7.73 (m, 2H), 7.81-7.88 (m, 2H), 8.02-8.08 (m, 2H), 8.21 (s,1H). MS (APCI+) m/z 451 (M+H)⁺.

EXAMPLE 1972-(4-Fluorophenyl)-4-(t-butylthiomethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A 0° C. solution of the2-(4-fluorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneprepared in Example 194F (92.5 mg, 0.212 mmol) in acetone (2.5 mL) wastreated with NaI (35 mg, 0.233 mmol), and after 5 minutes, the coolingbath was removed and the reaction warmed to 23° C. After 30 minutes,conversion to the2-(4-fluorophenyl)-4-iodomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonewas complete (thin layer chromatography, ethyl acetate/hexanes 4:1). TheNaBr and residual NaI were filtered off through a pad of Celite®.Additional acetone (2 mL) was added along with 2-methyl-2-propanethiol(20.5 mg, 0.227 mmol), and the solution cooled to 0° C. before additionof Ag₂CO₃ (63 mg, 0.227 mmol). After 5 minutes, the cooling bath wasremoved and the solution warmed to 23° C. for 5 hours. The reactionmixture was filtered through Celite® and concentrated in vacuo. Theresidue was chromatographed (flash silica gel, ethyl acetate/hexanesgradient 1:1 to 3:2) to provide the product (yield: 57 mg, 60%). mp50-70° C. ¹H NMR (300 MHz, CDCl₃) δ 1.34 (s, 9H), 3.14 (s, 3H), 3.65 (s,2H), 7.13-7.21 (m, 2H), 7.63-7.70 (m, 2H), 7.79 (s, 1H), 7.84 (d, J=8.7Hz, 2H), 8.13 (d, J=8.7 Hz, 2H). MS (APCI+) m/z 447 (M+H)⁺. Anal. calc.for C₂₂H₂₃FN₂O₃S₂: C, 59.17; H, 5.19; N, 6.27. Found: C, 59.48; H, 5.36;N, 5.90.

EXAMPLE 1982-(4-Fluorophenyl)-4-(2-methylpropylthiomethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone

The title compound was prepared according to the method of Example 197substituting 2-methyl-1-propanethiol in place of 2-methyl-2-propanethiol(yield: 66 mg, 70%). mp 45-60° C. ¹H NMR (300 MHz, CDCl₃) δ 0.95 (d,J=6.6 Hz, 6H), 1.67-1.82 (m, 1H), 2.62 (d, J=6.6 Hz, 2H), 3.15 (s, 3H),3.61 (s, 2H), 7.19 (dd, J=8.2, 8.2 Hz, 2H), 7.62-7.71 (m, 2H), 7.75 (d,J=8.4 Hz, 2H), 7.79 (s, 1H), 8.13 (d, J=8.4 Hz, 2H). MS (APCI+) m/z 447(M+H)⁺. Anal. calc. for C₂₂H₂₃FN₂O₃S₂: C, 59.17; H, 5.19; N, 6.27.Found: C, 59.35; H, 5.25; N, 6.05.

EXAMPLE 1992-(4-Fluorophenyl)-4-(2-propoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

The title compound was prepared by the following sequence of reactions.Mucobromic acid and 4-fluorophenylhydrazine hydrochloride were reactedto provide 2-(4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone followingthe procedure in Example 194A.

The dibromo intermediate was reacted according to the proceduredescribed in Example 194B, substituting isopropanol in place ofmethanol, to selectively react at the 4-position and provide2-(4-fluorophenyl)-4-(2-propoxy)-5-bromo-3(2H)-pyridazinone.

The 5-bromo-compound was coupled to 4-(methylthio)phenylboronic acidaccording to the method of Example 6 to provide the title compound(yield: 435 mg, 53.9%). mp 135-137° C. ¹H NMR (300 MHz, CDCl₃) δ 1.21(d, J=6 Hz, 6H), 2.55 (s, 3H), 5.26 (sept, J=6 Hz, 1H), 7.17 (t, J=9 Hz,2H), 7.34 (d, J=9 Hz, 2H), 7.57 (d, J=9 Hz, 2H), 7.58-7.66 (m, 2H), 7.95(s, 1H). MS (DCI/NH₃) m/z 371 (M+H)⁺.

EXAMPLE 2002-(4-Fluorophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The methyl sulfide compound prepared in Example 199 was oxidizedaccording to the method of Example 10 to provide the title compound(yield: 240 mg, 92%). mp 160-162° C. ¹H NMR (300 MHz, DMSO-d₆) δ 1.30(d, J=6 Hz, 6H), 3.41 (s, 3H), 5.41 (m, 1H), 7.48 (t, J=9 Hz, 2H), 7.77(dd, J=9 Hz, 6 Hz, 2H), 8.05 (d, J=9 Hz, 2H), 8.19 (d, J=9 Hz, 2H), 8.31(s, 1H). MS (DCI/NH₃) m/z 403 (M+H)⁺, 420 (M+NH₄)⁺. Anal. calc. forC₂₀H₁₉FN₂O₄S: C, 59.70; H, 4.73; N, 6.97. Found: C, 59.40; H, 4.86; N,6.69.

EXAMPLE 2012-(3-Chlorophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-(3-Chlorophenyl)-4-(2-propoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonewas prepared according to the method of Example 199, substituting3-chlorophenylhydrazine hydrochloride in place of4-fluorophenylhydrazine hydrochloride, in the first step. The resultingmethyl sulfide was oxidized according to the method of Example 10 toprovide the title compound (yield: 260 mg, 80%). mp 134-136° C. ¹H NMR(300 MHz, CDCl₃) δ 1.24 (d, J=6 Hz, 6H), 3.13 (s, 3H), 5.48 (sept, J=6Hz, 1H), 7.37-7.48 (m, 2H), 7.59 (dt, J=7-Hz, 1.5 Hz, 1H), 7.70 (br s,1H), 7.84 (d, J=9 Hz, 2H), 7.93 (s, 1H), 8.06 (d, J=9 Hz, 2H). MS(DCI/NH₃) m/z 419 (M+H)⁺, 436 (M+NH₄)⁺. Anal. calc. for C₂₀H₁₉ClN₂O₄S:C, 57.42; H, 4.55; N, 6.70. Found: C, 57.08; H, 4.59; N, 6.44.

EXAMPLE 2022-(3-Fluorophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The methyl sulfide intermediate was prepared according to the method ofExample 199, substituting 3-fluorophenylhydrazine hydrochloride in placeof 4-fluorophenylhydrazine hydrochloride in the first step. Theresulting methyl sulfide compound was oxidized according to the methodof Example 10 to provide the title compound (yield: 290 mg, 72%). mp110-112° C. ¹H NMR (300 MHz, CDCl₃) δ 1.31 (d, J=6 Hz, 6H), 3.11 (s,3H), 5.47 (sept, J=6 Hz, 1H), 7.09-7.18 (m, 1H), 7.41-7.52 (m, 3H), 7.83(d, J=9 Hz, 2H), 7.93 (s, 1H), 8.08 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z403 (M+H)⁺, 447 (M+NH₄)⁺. Anal. calc. for C₂₀H₁₉FN₂O₄S: C, 59.70; H,4.73; N, 6.97. Found: C, 59.54; H, 4.87; N, 6.70.

EXAMPLE 2032-(3-Bromophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The methyl sulfide intermediate was prepared according to the method ofExample 199, substituting 3-bromophenylhydrazine hydrochloride in placeof 4-fluorophenylhydrazine hydrochloride. The resulting methyl sulfidecompound was oxidized according to the method of Example 10 to providethe title compound (yield: 75 mg, 77.6%). mp 130-132° C. ¹H NMR (300MHz, CDCl₃) δ 1.23 (d, J=6 Hz, 6H), 3.15 (s, 3H), 5.48 (sept, J=6 Hz,1H), 7.38 (t, J=9 Hz, 1H), 7.55 (br d, J=7 Hz, 1H), 7.65 (br d, J=7 Hz,1H), 7.79-7.87 (m, 1H), 7.83 (d, J=9 Hz, 2H), 8.13 (s, 1H), 8.06 (d, J=9Hz, 2H). MS (DCI/NH₃) m/z 465 (M+H)⁺, 480 (M+NH₄)⁺. Anal. calc. forC₂₀H₁₉BrN₂O₄S: C, 51.84; H, 4.10; N, 6.05. Found: C, 51.95; H, 4.18; N,5.74.

EXAMPLE 2042-(2,5-Difluorophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-(2,5-Difluorophenyl)-4-(2-propoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonewas prepared according to the method of Example 199, substituting2,5-difluorophenylhydrazine hydrochloride in place of4-fluorophenylhydrazine hydrochloride.

The resulting methyl sulfide compound was oxidized according to themethod of Example 10 to provide the title compound (yield: 390 mg, 90%).mp 161-164° C. ¹H NMR (300 MHz, CDCl₃) δ 1.23 (d, J=6 Hz, 6H), 3.12 (s,3H), 5.55 (sept, J=6 Hz, 1H), 7.12-7.29 (m, 3H), 7.82 (d, J=9 Hz, 2H),7.92 (s, 1H), 8.07 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 421 (M+H)⁺, 438(M+NH₄)⁺. Anal. calc. for C₂₀H₁₈F₂N₂O₄S.0.5H₂O: C, 55.94; H, 4.31; N,6.53. Found: C, 55.86; H, 4.19; N, 6.38.

EXAMPLE 2052-(3-Chloro-4-fluorophenyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared by the following sequence of reactions.Mucobromic acid and 3-chloro-4-fluorophenylhydrazine hydrochloride werereacted to provide2-(3-chloro-4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone according tothe method of Example 194A.

The intermediate was selectively reacted at the 4-position withisobutanol and base to provide2-(4-fluorophenyl)-4-[1-(2-methylpropoxy)]-5-bromo-3(2H)-pyridazinoneaccording to the method of Example 194B

The 5-bromo-compound was coupled to 3-fluoro-4-(methylthio)phenylboronicacid prepared in Example 194C according to the method of Example 6 toproduce the intermediate methyl sulfide. The sulfide compound wasoxidized to the title methyl sulfone according to the method of Example10 (yield: 810 mg, 83.8%). mp 142-144° C. ¹H NMR (300 MHz, CDCl₃) δ 0.90(d, J=6 Hz, 6H), 1.95 (sept, J=6 Hz, 1H), 3.30 (s, 3H), 4.37 (d, J=6 Hz,2H), 7.26 (t, J=9 Hz, 1H), 7.52-7.61 (m, 3H), 7.75 (dd, J=9 Hz, 3 Hz,1H), 7.89 (s, 1H), 8.10 (t, J=9 Hz, 1H). MS (DCI/NH₃) m/z 469 (M+H)⁺,486 (M+NH₄)⁺.

EXAMPLE 2062-(3,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylsulfonyl)phenyl]3(2H)-pyridazinoneEXAMPLE 206A 2-Methylthioanisole

A solution of 2-bromothioanisole (10.53 g, 52 mmol) in tetrahydrofuran(173 mL) was prepared and cooled to −78° C. n-BuLi (21.8 mL, 54.5 mmol,2.5 M solution in hexanes) was slowly added along the interior wall ofthe reaction vessel. The resultant light yellow solution was stirred for30 minutes before methyl iodide (8.10 g, 57.1 mmol) diluted withtetrahydrofuran (6 mL) was slowly added along the interior wall of thereaction vessel. The mixture was stirred for another 30 minutes at −78°C. The cooling bath was removed, and the mixture stirred for 1 hour. Thesolution was cooled to 0° C. and a saturated aqueous NH₄Cl solutionadded. The resultant solution was extracted several times with ethylacetate, and the combined acetate layers washed with brine, dried overMgSO₄, filtered, and concentrated in vacuo. The residue waschromatographed (flash silica gel, ethyl acetate/hexanes 1:19) toprovide the product (yield: 6.74 g, 94%). ¹H NMR (300 MHz, CDCl₃) δ 2.34(s, 3H), 2.46 (s, 3H), 7.02-7.09 (m, 1H), 7.12-7.22 (m, 3H).

EXAMPLE 206B 4-Bromo-2-methylthioanisole

To a 0° C. solution of 2-methylthioanisole (0.50 g, 3.57 mmol) inmethylene chloride (40 mL) was added powdered Fe (20 mg, 0.36 mmol)followed by dropwise addition of bromine (0.58 g, 3.54 mmol). After 30minutes, the starting material had been consumed (thin layerchromatography, hexanes). The excess bromine was quenched by adding asolution of NaHSO₃ and stirring for several minutes. The methylenechloride layer was separated, and the aqueous phase extracted withadditional methylene chloride. The combined methylene chloride solutionwas dried over MgSO₄, filtered, and concentrated in vacuo. The resultantoil was chromatographed (flash silica gel, ethyl acetate/hexanes 1:49)to provide the product (yield: 0.74 g, 96%). ¹H NMR (300 MHz, CDCl₃) δ2.30 (s, 3H), 2.45 (s, 3H), 7.00 (d, J=8.4 Hz, 1H), 7.27-7.33 (m, 2H).

EXAMPLE 206C 3-Methyl-4-(methylthio)benzeneboronic acid

3-Methyl-4-(methylthio)benzeneboronic acid was prepared according to themethod of Example 1, substituting 4-bromo-2-(methylthio)anisole in placeof 4-bromothioanisole (yield: 5.3 g, 67%). mp 208-210. ¹H NMR 2.28 (s,3H), 2.46 (s, 3H), 7.20 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.70 (d, J=8.4Hz, 1H).

EXAMPLE 206D 2-(3,4-Difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 194A,substituting 3,4-difluorophenyl hydrazine.HCl in place of 4-fluorophenylhydrazine-HCl (yield: 39 g, 78%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.45 (m,1H), 7.61 (m, 1H), 7.75 (m, 8.30 (s, 1H). MS (DCI/NH₃) m/z 382 (M+NH₄)⁺.

EXAMPLE 206E 2-(3,4-Difluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 194B,substituting 2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone inplace of 2-(4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone (yield: 15mg, 88%). ¹H NMR (300 MHz, DMSO-d₆) δ 4.14 (s, 3H), 7.45 (m, 1H), 7.60(m, 1H), 7.74 (m, 1H), 8.24 (s, 1H). MS (DCI/NH₃) m/z 317 (M+H)⁺ and m/z334 (M+NH₄)⁺.

EXAMPLE 206F2-(3,4-Difluorophenyl)-4-methoxy-5-[3-methyl-4-(methylthio)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 6starting with2-(3,4-difluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone in place of2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone and substituting3-methyl-4-(methylthio)benzeneboronic acid in place of4-fluorobenzeneboronic acid (yield: 2.0 g, 85%). ¹H NMR (300 MHz, CDCl₃)δ 2.39 (s, 3H), 2.53 (s, 3H), 4.11 (s, 3H), 7.22-7.32 (m, 2H), 7.34 (s,1H), 7.42-7.50 (m, 2H), 7.55-7.64 (m, 1H), 7.92 (s, 1H). MS (APCI+) m/z375 (M+H)⁺.

EXAMPLE 206G2-(3,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylthio)phenyl]-3(2H)-pyridazinone

2-(3,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylthio)phenyl]-3(2H)-pyridazinone,was prepared according to the method of Example 228, starting with2-(3,4-difluorophenyl)-4-methoxy-5-[3-methyl-4-(methylthio)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneand substituting 4-fluorophenyl magnesium bromide in place ofcyclohexylmagnesium chloride (yield: 330 mg, 56%). ¹H NMR (300 MHz,CDCl₃) δ 2.24 (s, 3H), 2.47 (s, 3H), 6.90-7.03 (m, 6H), 7.22-7.31 (m,2H), 7.49-7.54 (m, 1H), 7.60-7.68 (m, 1H), 8.02 (s, 1H). MS (APCI+) m/z439 (M+H)⁺.

EXAMPLE 206H2-(3,4-Difluoro-phenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 10,substituting2-(3,4-difluorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylthio)phenyl]-3(2H)-pyridazinonein place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(yield: 251 mg, 82%) mp 80-100° C. ¹H NMR (300 MHz, DMSO-d₆) δ 2.59 (s,3H), 3.25 (s, 3H), 7.13-7.34 (m, 5H), 7.45 (s, 1H), 7.52-7.69 (m, 2H),7.81 (d, J=8.4 Hz, 1H), 7.81-7.90 (m, 1H), 8.27 (s, 1H). MS (APCI+) m/z471 (M+H)⁺ and m/z 488 (M+NH₄)⁺. Anal. calc. for C₂₄H₁₇F₃N₂O₃S: C,61.27; H, 3.64; N, 5.95. Found: C, 61.53; H, 3.92; N, 5.67.

EXAMPLE 2072-(3-Chlorophenyl)-4-(4-fluorophenoxymethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 207A 2-(3-Chlorophenyl)-4,5-dibromo-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 194A,substituting 3-chlorophenyl hydrazine HCl in place of 4-fluorophenylhydrazine.HCl (yield: 24.8 g, 88%). ¹H NMR (300 MHz, DMSO-d₆) δ7.53-7.57 (m, 3H), 7.67-7.70 (m, 1H), 8.29 (s, 1H). MS (DCI/NH₃) m/z 365(M+H)⁺ and m/z 382 (M+NH₄ ⁺)⁺.

EXAMPLE 207B 2-(3-Chlorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 194B,substituting 2-(3-chlorophenyl)-4,5-dibromo-3(2H)-pyridazinone in placeof 2-(4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone (yield: 12.4 g,95%). ¹H NMR (300 MHz, DMSO-d₆) δ 4.21 (s, 3H), 7.58-7.62 (m, 3H),7.73-7.76 (m, 1H), 8.28 (s, 1H). MS (DCI/NH₃) m/z 317 (M+H)⁺ and m/z 334(M+NH₄ ⁺)⁺.

EXAMPLE 207C2-(3-Chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 6starting with 2-(3-chlorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone inplace of 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone and substituting4-(methylthio)benzeneboronic acid in place of 4-fluorobenzeneboronicacid (yield: 3.3 g, 68%). ¹H NMR (300 MHz, DMSO-d₆) δ 2.54 (s, 3H), 4.03(s, 3H), 7.40 (d, J=9.0 Hz, 2H), 7.50-7.64 (m, 5H), 7.73-7.77 (m, 1H),8.18 (s, 1H). MS (DCI/NH₃) m/z 359 (+H)⁺.

EXAMPLE 207D2-(3-Chlorophenyl)-4-methyl-5-r[3-methyl-4-(methylthio)phenyl]-3(2H)-pyridazinone

2-(3-Chlorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylthio)phenyl]-3(2H)-pyridazinone,was prepared according to the method of Example 228, starting with2-(3-chlorophenyl)-4-methoxy-5-[3-methyl-4-(methylthio)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneand substituting 4-fluorophenyl magnesium bromide in place ofcyclohexylmagnesium chloride (yield: 180 mg, 94%). ¹H NMR (300 MHz,CDCl₃) δ 2.25 (s, 3H), 2.56 (s, 3H), 7.28-7.45 (m, 6H), 7.58-7.63 (m,1H), 7.71-7.74 (m, 1H), 7.82 (s, 1H). MS (APCI+) m/z 343 (M+H)⁺ and m/z360 (M+NH₄)⁺.

EXAMPLE 207E2-(3-Chlorophenyl)-4-methyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 10,substituting2-(3-chlorophenyl)-4-methyl-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonefor2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(yield: 125 mg, 67%). mp 164-168. ¹H NMR (300 MHz, CDCl₃) δ 2.23 (s,3H), 3.13 (s, 3H), 7.37-7.46 (m, 2H), 7.61 (m, 3H), 7.71-7.74 (m, 1H),7.81 (s, 1H), 8.13 (d, J=8.7 Hz, 2H). MS (APCI+) m/z 343 (M+H)⁺ and m/z360 (M+NH₄)⁺.

EXAMPLE 207F2-(3-Chlorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-(3-Chlorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonewas prepared according to the method of Example 194F, substituting2-(3-chlorophenyl)-4-methyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-methyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 90 mg, 99%). ¹H NMR (300 m/z, CDCl₃) δ 3.13 (s, 3H), 4.33 (s,2H), 7.40-7.47 (m, 2H), 7.66 (ddd, J=2.4, 2.4, 7.2 Hz, 1H), 7.76-7.78(m, 1H), 7.81 (d, J=8.7 Hz, 2H), 7.86 (s, 1H), 8.17 (d, J=8.7 Hz, 2H).MS (APCI+) m/z 453 (M+H)⁺ and m/z 470 (M+NH₄)⁺.

EXAMPLE 207G2-(3-Chlorophenyl)-4-(4-fluorophenoxymethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 194G,substituting2-(3-chlorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 30 mg, 31%). mp 50-80° C. ¹H NMR (300 MHz, CDCl₃) δ 3.11 (s,3H), 4.94 (s, 2H), 6.78-6.85 (m, 2H), 6.91-6.99 (m, 2H), 7.39-7.48 (m,2H), 7.64 (ddd, J=7.5, 1.9, 1.9 Hz, 1H), 7.71-7.77 (m, 3H), 7.93 (s,1H), 8.08 (d, J=8.7 Hz, 2H). MS (APCI+) m/z 485 (M+H)⁺.

EXAMPLE 2082-(3-Chlorophenyl)-4-(benzoyloxymethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 207substituting benzoic acid in place of 4-fluorophenol (yield: 33 mg,34%). mp 50-70° C. —H NMR (300 MHz, CDCl₃) δ 3.00 (s, 3H), 5.36 (s, 2H),7.36-7.48 (m, 4H), 7.52-7.59 (m, 1H), 7.61-7.68 (m, 3H), 7.75-7.78 (m,1H), 7.83-7.88 (m, 2H), 7.89 (s, 1H), 8.02 (d, J=8.7 Hz, 2H). MS (APCI+)m/z 495 (M+H)⁺.

EXAMPLE 2092-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone

The title compound was prepared according to the method of Example 193,substituting 1-bromo-3-methylbutane in place of 4-fluorobenzyl bromide(yield: 80 mg, 19%). ¹H NMR (300 MHz, CDCl₃) δ 0.81 (d, J=7.5 Hz, 6H),1.3-1.6 (m, 3H), 2.52 (m, 2H), 3.14 (3H, s) 4.85 (q, J=9 Hz, 2H), 7.55(d, J=9 Hz, 2H) 7.67 (s, 1H), 8.1 (d, J=9 Hz, 2H). MS (DCI/NH₃), m/z 403(M+H)⁺. Anal. calc. for C₁₈H₂₁F₃N₂O₃S.0.25H₂O: C, 53.12; H, 5.32; N,6.88. Found C, 52.90; H, 5.14; N, 6.43.

EXAMPLE 2102-(2,2,2-Trifluoroethyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 210A 4-fluoro-3-methylbenzeneboronic acid

-   5-Bromo-2-fluorotoluene (6 g, 31.7 mmol) was dissolved in dry THF    (50 mL) and cooled to −78 C under N₂. n-BuLi (14 mL, 2.5M solution    in THF) was added slowly using a dry syringe. Cloudiness appeared.    The reaction was stirred for 40 minutes at −78° C. Triisopropyl    borate (22 mL, 95 mmol) was slowly added while stirring. The    reaction was allowed to warm to room temperature. Stirring continued    for an additional 2 hours. A pale yellow, cloudy solution formed.    (TLC (1:2 ethyl acetate/hexanes)) indicated disappearance of the    starting material. The reaction was quenched by adding 10% aqueous    NaOH (200 mL). After stirring for 45 minutes, 10% citric acid    solution (300 mL) was added until, pH ˜5.0. The product was    extracted with ethyl acetate (500 mL). The organic phase was washed    with brine and dried over MgSO₄, and filtered. The filtrate was    concentrated under reduced pressure to provide an off white solid    (yield: 4.1 g, 84%).

EXAMPLE 210B2-(2,2,2-trifluoroethyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone

The boronic acid (231 mg, 1.5 mmol), prepared in example 210A,2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(500 mg, 1.36 mmol), tetrakis-(triphenylphosphine)-palladium(0) (47 mg,0.041 mmol), and CsF (413 mg, 2.72 mmol) were stirred at reflux in DME(20 mL) under N₂ for 5 hours. TLC (1:1 hexanes/ethyl acetate) indicatedthat all the starting material was consumed. Volatiles were removed invacuo. The residue was partitioned between water and ethyl acetate. Theorganic layer was washed with brine, dried over MgSO₄, and filtered. Thefiltrate was concentrated in vacuo. An off white powder was obtained(yield: 275 mg, 46%). mp 88-91° C.; ¹H NMR (300 MHz, CDCl₃, a mixture ofrotamers) δ 2.2, 2.25 (2d, J=1.5 Hz, 3H) 3.05, 3.09 (2 s, 3H) 4.78-4.92(m, 2H) 6.61-6.8 (m, 1H) 6.82-6.98 (m, 1H) 7.35 (d, J=9 Hz, 1H) 7.78 (d,J=9 Hz, 1H) 7.86-8.09 (m, 4H). MS (DCI/NH₃), m/z 441 (M+H)⁺. Anal. calc.for C₂₀H₁₆F₄N₂O₃S.0.5H₂O: C, 53.45; H, 3.81; N, 6.23. Found C, 53.17; H,3.65; N, 5.88.

EXAMPLE 2112-(2,2,2-Trifluoroethyl)-4-(3,5-dichlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(150 mg, 0.409 mmol) (Example 193E) was dissolved in anhydrous DME (8mL) and heated to reflux with 3,5-dichlorobenzeneboronic acid inpresence of CsF (150 mg, 0.98 mmol) andtetrakis(triphenylphosphine)-palladium (17.38 mg, 0.015 mmol) for 6hours. After cooling to room temperature the reaction mixture wasdiluted with water and extracted with ethyl acetate (100 mL). Theorganic layer was washed with brine, dried over MgSO₄, and evaporated invacuo. The compound was purified on a silica gel column, eluting with30% ethyl acetate in pentanes, to provide the title compound (yield: 110mg, 58%). ¹H NMR (300 MHz, CDCl₃) δ3.08 (s, 3H), 4.88 (q, J=9 Hz, 2H),7.06 (d, J=1.5 Hz, 9 Hz, 2H), 7.31 (t, J=1.5 Hz, 1H), 7.36 (d, J=9 Hz,2H), 7.94 (s, 1H), 7.96 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 496 (M+NH₄)⁺.Anal. calc. for C₁₉H₁₃Cl₂F₃N₂O₃S: C, 47.81; H, 2.75; N, 5.87. Found: C,47.77; H, 2.75; N, 5.65

EXAMPLE 2122-(2,2,2-Trifluoroethyl)-4-(3-ethoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 211,substituting 3-ethoxyphenylboronic acid for 3,5-dichlorobenzeneboronicacid (yield: 155 mg, 86%). ¹H NMR (300 MHz, CDCl₃) δ 1.42 (t, J=7.5 Hz,3H), 3.06 (s, 3H), 3.90 (q, J=7.5 Hz, 2H), 4.88 (q, J=9 Hz, 2H), 6.65(d, J=7.5 Hz, 1H), 6.75 (t, J=1.5 Hz, 1H), 6.85 (dd, J=1.5 Hz, 9 Hz,1H), 7.15 (t, J=9 Hz, 1H), 7.38 (d, J=39 Hz, 2H), 7.88 (d, J=9 Hz, 2H),7.90 (s, 1H). MS (DCI/NH₃) m/z 470 M+NH₄)⁺. Anal. calc. forC₂₁H₁₉Cl₂F₃N₂O₄S: C, 55.75; H, 4.23; N, 6.19. Found: C, 55.62; H, 4.30;N, 5.99

EXAMPLE 2132-(2,2,2-Trifluoroethyl)-4-(4-trifluoromethylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 211,substituting 4-(trifluoromethyl)benzeneboronic acid in place of3,5-dichlorobenzeneboronic acid (yield: 85 mg, 44%). ¹H NMR (300 MHz,CDCl₃) δ 3.08 (s, 3H), 4.90 (q, J=9 Hz, 2H), 7.35 (t, J=9 Hz, 4H), 7.58(d, J=9 Hz, 2H), 7.90 (d, J=9 Hz, 3H). MS (DCI/NH₃) m/z 494 (M+NH₄)⁺.Anal. calc. for C₂₀H₁₄F₆N₂O₃S: C, 50.42; H, 2.96; N, 5.88. Found: C,50.20; H, 3.02; N, 5.70

EXAMPLE 2142-(2,2,2-Trifluoroethyl)-4-(3-nitrophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 211,substituting 3-nitrobenzeneboronic acid in place of3,5-dichlorobenzeneboronic acid (yield: 40 mg, 22%). ¹H NMR (300 MHz,CDCl₃) 6.3.05 (s, 3H), 4.92 (q, J=9 Hz, 2H), 7.36 (d, J=9 Hz, 2H),7.45-7.60 (m, 2H), 7.91 (d, J=9 Hz, 2H), 7.95 (s, 1H), 8.05 (m, 1H),8.15-8.21 (m, 1H). MS (DCI/NH₃) m/z 471 (M+NH₄)⁺. Anal. calc. forC₁₉H₁₄Cl₂F₃N₃O₅S.0.5 EtOAc: C, 50.70; H, 3.64; N, 8.44. Found: C, 50.61;H, 3.58; N, 8.53

EXAMPLE 2152-(2,2,2-Trifluoroethyl)-4-(2-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 211,substituting 2-methylbenzeneboronic acid in place of3,5-dichlorobenzeneboronic acid (yield: 45 mg, 27%). ¹H NMR (300 MHz,CDCl₃) δ 2.05, 2.12 (2s, 3H), 3.01 (s, 3H), 4.75-5.05 (m, 2H), 6.88 (d,J=9 Hz, 1H), 7.03-7.25 (m, 3H), 7.31 (d, J=9 Hz, 2H), 7.85 (d, J=9 Hz,2H), 7.95 (s, 1H). MS (DCI/NH₃) m/z 440 (M+NH₄)⁺. Anal. calc. forC₂₀H₁₇F₃N₂O₃S: C, 55.10; H, 4.27; N, 6.42. Found: C, 55.17; H, 4.18;N-6.10

EXAMPLE 2162-(2,2,2-Trifluoroethyl)-4-(4-vinylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 211,substituting 4-vinylbenzeneboronic acid in place of3,5-dichlorobenzeneboronic acid (yield: 56 mg, 32%). ¹H NMR (300 MHz,CDCl₃) δ 3.06, 3.08 (2s, 3H), 4.78-4.95 (m, 2H), 5.30 (t, J=6 Hz, 1H),5.65, 5.75 (2d, J=18 Hz, 1H), 6.58-6.92 (m, 1H), 7.1-7.4 (m, 6H),7.75-8.08 (m, 3H). MS (DCI/NH₃) m/z 452 (M+NH₄)⁺. Anal. calc. forC₂₁H₁₇F₃N₂O₃S: C, 58.06; H, 3.94; N, 6.45. Found: C, 57.82; H, 4.01; N,6.09

EXAMPLE 2172-(2,2,2-Trifluoroethyl)-4-[3-(trifluoromethyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 211substituting 3-trifluoromethylbenzeneboronic acid in place of3,5-dichlorobenzeneboronic acid (yield: 120 mg, 63%). ¹H NMR (300 MHz,CDCl₃) δ 3.03, 3.08 (2s, 3H), 4.75-4.98 (m, 2H), 7.30-7.60 (m, 6H),7.75-8.10 (m, 3H). MS (DCI/NH₃) m/z 494 (M+NH₄)⁺. Anal. calc. forC₂₀H₁₄F₆N₂O₃S: C, 50.42; H, 2.96; N, 5.88. Found: C, 50.38; H, 2.97; N,5.74

EXAMPLE 2182-(2,2,2-Trifluoroethyl)-4-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 211,substituting 3-fluoro-4-methoxybenzeneboronic acid in place of3,5-dichlorobenzeneboronic acid (yield: 32 mg, 18%). ¹H NMR (300 MHz,CDCl₃) δ 3.05, 3.09 (2s, 3H), 3.85, 3.87 (2s, 3H), 4.78-4.90 (m, 2H),6.60-7.10 (m, 3H), 7.30-8.15 (m, 5H). MS (DCI/NH₃) m/z 474 (M+NH₄)⁺.Anal. calc. for C₂₀H₁₆F₄N₂O₄S.0.5H₂O: C, 51.61; H, 3.68; N, 6.01. Found:C, 51.52; H, 3.65; N, 5.93

EXAMPLE 2192-(2,2,2-Trifluoroethyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 211substituting 3-fluoro-4-methylbenzeneboronic acid in place of3,5-dichlorobenzeneboronic acid (yield: 58 mg, 33%). ¹H NMR (300 MHz,CDCl₃) δ 2.21, 2.25 (2d, J=1.5 Hz, 3H), 3.50, 3.55 (2s, 3H), 4.75-4.95(m, 2H), 6.56-7.15 (m, 3H), 7.30-8.10 (m, 5H). MS (DCI/NH₃) m/z 458(M+NH₄)⁺. Anal. calc. for C₂₀H₁₆F₄N₂O₃S.0.5H₂O: C, 53.45; H, 3.81; N,6.23. Found: C, 53.14; H, 3.80; N, 5.97

EXAMPLE 2202-(2,2,2-Trifluoroethyl)-4-(3,5-difluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 211,substituting 3,5-difluoro-4-methoxybenzeneboronic acid in place of3,5-dichlorobenzeneboronic acid. ¹H NMR (300 MHz, CDCl₃) δ 2.9, 3.1 (2s,3H), 3.92, 4.01 (2s, 3H), 4.78-4.95 (m, 2H), 6.25-6.80 (m, 1H), 7.30-7.5(m, 2H), 7.7-8.15 (m, 4H). MS (DCI/NH₃) m/z 492 (M+NH₄)⁺. Anal. calc.for C₂₀H₁₅F₅N₂O₄S: C, 50.64; H, 3.19; N, 5.90. Found: C, 50.542; H,3.41; N, 5.67

EXAMPLE 2212-(2,2,2-Trifluoroethyl)-4-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

6-Bromophthalide (300 mg, 1.40 mmol, Teppema et al Recl. Trav. Chim.Pays-Bays, (1923) 42, 47) and hexamethylditin (326 μL, 1.55 mmol) weredissolved in toluene (5 mL), degassed with a nitrogen stream for 5minutes, treated with (h₃P)₄Pd (79 mg) and heated at reflux for 1 hour.The reaction was cooled and directly purified by chromatography on aBiotage 40S column (pretreated with hexanes-TEA 400:1 then rinsed withhexanes) eluted with 4:1 hexanes-ethyl acetate. The product fractionswere combined and evaporated to provide 6-(trimethyltin)phthalide(yield: 362 mg, 87%).

The tin reagent (180 mg, 0.61 mmol), prepared above, and2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone,prepared in Example 193E, (223 mg, 0.61 mmol) were dissolved in drytoluene (1.0 mL), degassed with an nitrogen stream for 5 minutes,treated with (Ph₃P)₄Pd (34 mg) and heated at reflux for 1 day. Thereaction was cooled and directly purified by chromatography on a Biotage40S column eluted with 4:1 hexanes-ethyl acetate. The product fractionswere combined and evaporated to provide the title compound along withthe 4-(1,3-dihydro-1-oxo-6-isobenzofuranyl)-isomer in a 9:1 ratio.Further manipulations to attempt to remove the minor isomer (i.e.chromatography, recrystallization from ethyl acetate-hexanes) failed(yield: 176 mg, 62%). mp 237-239° C. ¹H NMR (300 MHz, CDCl₃) δ 3.07 (s,3H), 4.91 (q, J=8 Hz, 2H), 5.30 (s, 2H, major isomer), 5.33 (s, 2H,minor isomer), 7.20 (dd, J=1 Hz, 7 Hz, 1H), 7.36 (d, J=8 Hz, 2H), 7.52(s, 1H), 7.79 (d, J=7 Hz, 1H), 7.92 (d, J=8 Hz, 2H), 7.96 (s, 1H). MS(DCI/NH₃) m/z 482 (M+NH₄)⁺. Anal. calc. for C₂₁H₁₅F₃N₂O₅S: C, 54.31; H,3.26; N, 6.03. Found: C, 54.15; H, 3.12; N, 5.76.

EXAMPLE 2222-(2,2,2-Trifluoroethyl)-4-(2-propenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A suspension of2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(200 mg, 0.546 mmol), prepared according to the method of Example 193E,in THF (27 mL) was cooled to −78° C. A solution of isopropenylmagnesiumbromide (2.8 mL, 0.5 M in THF, Aldrich) was added. The reaction waswarmed to room temperature and stirred for 30 minutes. The reaction wasquenched at 0° C. by the addition of saturated ammonium chloridesolution and partitioned between ethyl acetate and additional ammoniumchloride solution. The organic layer was washed with brine, dried oversodium sulfate, filtered, and concentrated under reduced pressure toprovide a reddish brown solid. The crude material was dissolved inmethylene chloride and adsorbed onto silica gel (2 g). Solvent wasremoved under reduced pressure, the adsorbed silica gel layered over anExtract-Clean Cartridge® (Alltech, packing: 5 g silica gel) and thecartridge eluted with a hexanes/acetone step gradient consisting of 40mL of the following mixtures: hexanes, 8:1 hexanes/acetone, 4:1, 2:1,and 1:1. Fractions containing desired product were combined,concentrated, and further purified using HPLC (Technikrom Kromasil 60-5sil column, 20 mm×25 cm). The column was eluted with a linear gradientconsisting of 30% ethyl acetate/hexanes to 100% ethyl acetate at 10mL/min over 50 minutes. Fractions containing the title product werecombined and concentrated under reduced pressure to provide a paleyellow solid (yield: 99.3 mg, 49%). mp 192-195° C. ¹H NMR (300 MHz,CDCl₃) δ 8.03 (d, J=17.4 Hz, 2H), 7.76 (s, 1H), 7.55 (d, 2H, J=17.4 Hz),5.23 (br s, 1H), 4.84 (m, 3H), 3.11 (s, 3H), 1.98 (s, 3H). MS (DCI/NH₃)m/z 373 (M+H)⁺, m/z 390 (M+NH₄)⁺. Anal. calc. for C₁₆H₁₅F₃N₂O₃S: C,51.61; H, 4.06; N, 7.52. Found: C, 51.72; H, 4.24; N, 7.35.

EXAMPLE 2232-(2,2,2-Trifluoroethyl)-4-(2-buten-2-yl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 222substituting 1-methyl-1-propenylmagnesium bromide in place ofisopropenylmagnesium bromide to provide a mixture of geometric isomers(−3:1 ratio) as an off-white solid (yield: 44.8 mg, 21%). mp 175-180° C.¹H NMR (300 MHz, CDCl₃) δ58.03 (d, J=18.0 Hz, 1.5H), 8.01 (d, J=18.0 Hz,0.5H), 7.29 (5, 0.75H), 7.28 (s, 0.25H), 7.56 (d, J=17.4 Hz, 1.5H), 7.51(d, J=17.4 Hz, 0.5H), 5.55 (m, 0.75H)-5.33 (m, 0.25H), 5.86 (q, J=17.4Hz, 2H), 3.12 (s, 2.25H), 3.11 (s, 0.75H), 2.88 (m, 2H), 2.85 (m, 1H),1.27 (m, 3H). MS (DCI/NH₃) m/Z 387 (M+H)⁺, m/z 404 (M+NH₄)⁺, m/z 421(M+2NH—H)⁺. Anal. calc. for C₁₇H₁₇F₃N₂O₃S: C, 52.85; H, 4.43; N, 7.25.Found: C, 53.16; H, 4.68; N, 6.92.

EXAMPLE 2242-(2,2,2-Trifluoroethyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 224A 3-Fluorobenzyl magnesium bromide

3-Fluorobenzyl bromide (613 μL, 5 mmol), followed by dibromoethane (10μL), was added dropwise to an oven-dried flask containing small piecesof magnesium ribbon (134 mg, 5.5 mmol) and diethyl ether (12 mL). Gasevolution was noted followed by gentle reflux of the ether. The reactionwas stirred until gas evolution ceased and most of the magnesium haddissolved. The resulting pale yellow solution of 3-fluorobenzylmagnesiumbromide was used directly in the next reaction.

EXAMPLE 224B2-(2,2,2-Trifluoroethyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A suspension of2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(200 mg, 0.546 mmol), prepared according to the method of Example 193E,in THF (10 mL) was cooled to 0° C. A solution of 3-fluorobenzylmagnesium bromide (4.0 mL, ˜0.42 M in diethyl ether), prepared above wasadded. The reaction was stirred at 0° C. for 3 hours, quenched by theaddition of saturated ammonium chloride solution, and partitioned,between ethyl acetate and additional ammonium chloride solution. Theorganic layer was washed with brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure to provide a yellowoil. The crude material was dissolved in methylene chloride and adsorbedonto silica gel (2 g). Solvent was removed under reduced pressure, thesilica gel with the product adsorbed was layered over an Extract-CleanCartridge® (Alltech, packing: 10 g silica gel) and the cartridge elutedwith a hexanes/acetone step gradient consisting of 60 mL of each of thefollowing mixtures: hexanes, 8:1 hexanes/acetone, 4:1, 2:1, and 1:1.Fractions containing desired product were combined, concentrated, andfurther purified using HPLC (Technikrom Kromasil 60-5 sil silica column,20 mm×25 cm). The column was eluted with a linear gradient consisting of30% ethyl acetate/hexanes to 100% ethyl acetate at 10 mL/min. for 50minutes. Fractions containing the title product were combined andconcentrated under reduced pressure to provide a pale yellow solid(yield: 130.9 mg, 54%). mp 58-62° C. ¹H NMR (300 MHz, CDCl₃) δ 8.07 (d,J=18.0 Hz, 2H), 7.73 (s, 1H), 7.47 (d, J=17.4 Hz, 2H), 7.18 (m, 1H),6.88 (m, 1H), 6.76 (br d, J=15.6 Hz, 1H), 6.68 (br d, J=18.6 Hz, 1H),4.86 (q; J=17.4 Hz, 2H), 3.93 (s, 2H), 3.12 (s, 3H). MS (DCI/NH₃) m/z441 (M+H)⁺, m/z 458 (M+NH₄)⁺, m/z 475 (M+2NH₄—H)⁺. Anal. calc. forC₂₀H₁₆F₄N₂O₃S: C, 54.54; H, 3.66; N, 6.36. Found: C, 54.52; H, 3.81; N,6.17.

EXAMPLE 2252-(2,2,2-Trifluoroethyl)-4-(1-cyclohexenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 225A 1-Cyclohexenyltriflate

n-Butyllithium (2.5M in hexanes, 2.20 mL, 5.50 mmol) was added to asolution of diisopropylamine (0.77 mL, 5.50 mmol) in THF (20 mL) at −78°C. The resulting pale yellow solution was warmed to 0° C. for 30 minutesthen was cooled to −78° C. Cyclohexanone (0.52 mL, 5.0 mmol) was addedand the nearly colorless solution was warmed to 0° C. for 1 hour.N-Phenyltrifluoromethanesulfonimide (1.79 g, 5.5 mmol) was added as asolid. The solution was stirred at room temperature for 12 hours. Thereaction mixture was then partitioned between diethyl ether andsaturated sodium bicarbonate solution. The ether layer was washed withwater then brine, dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The crude material was purified by flashchromatography (20:1 hexanes/ethyl acetate) to provide the triflate as apale yellow oil (yield: 0.73 g, 64%).

EXAMPLE 225B 1-Cyclohexenyltrimethyltin

A solution of 1-cyclohexenyltriflate (412 mg, 1.79 mmol), preparedaccording to the method of Example 225A, and LiCl (380 mg, 8.95 mmol) inTHF (9 mL) was deoxygenated by bubbling a stream of N₂ through thesolution. Hexamethylditin (339 μL, 1.61 mmol) andtetrakis(triphenylphosphine)palladium(0) (414 mg, 0.36 mmol) were addedand the reaction heated at reflux for 12 hours. The reaction was cooledto room temperature and partitioned between diethyl ether and saturatedsodium bicarbonate solution. The ether layer was washed with water thenbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The crude material was dissolved in hexanes (1 mL) andloaded onto an Extract-Clean Cartridge® (Alltech, packing: 10 g silicagel) which had been wetted with 10% triethylamine in hexanes. Thecartridge was eluted with hexanes and fractions containing the triflatecombined and concentrated under reduced pressure to provide1-cyclohexenyltrimethyltin as a clear oil (yield: 150 mg, 34%).

EXAMPLE 225C2-(2,2,2-Trifluoroethyl)-4-(1-cyclohexenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A solution of 1-cyclohexenyltrimethyltin (150 mg, 0.61=mol), preparedaccording to the method of Example 225B, and2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(172 mg, 0.47 mmol), prepared according to the method of Example 193E,in anhydrous N-methylpyrrolidinone (1 mL) was deoxygenated withnitrogen. Dichlorobis(triphenylphosphine) palladium(II) (6.6 mg, 0.009mmol) and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II)(7.7 mg, 0.009 mmol) were added and the reaction heated at 80° C. for 16hours. The reaction mixture was cooled to room temperature andpartitioned between diethyl ether and water. The ether was washed withtwo additional portions water then brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude materialwas dissolved in acetone and adsorbed onto silica gel (1 g). Solvent wasremoved under reduced pressure, the adsorbed silica gel layered over anExtract-Clean Cartridge®(Alltech, packing: 10 g silica gel) and thecartridge eluted with a hexanes/acetone step gradient consisting of thefollowing mixtures: hexanes (60 mL), 8:1 hexanes/acetone (80 mL), 4:1hexanes/acetone (150 mL). Fractions containing desired product werecombined, concentrated, and further purified using HPLC (TechnikromKromasil 60-5 sil silica column, 20 mm×25 cm). The column was elutedwith a linear gradient consisting of 30% ethyl acetate/hexanes to 100%ethyl acetate at 10 mL/min. over 50 minutes. Fractions containing thetitle product were combined and concentrated under reduced pressure toprovide a pale yellow foam (yield: 95.0 mg, 49%). mp 75-81° C. ¹H NMR(300 MHz, CDCl₃) δ 8.02 (d, J=17.4 Hz, 2H), 7.76 (s, 1H), 7.55 (d,J=17.4 Hz, 2H), 5.51 (br s, 1H), 4.83 (br q, J=16.2 Hz, 3H), 3.11 (s,3H), 2.18 (br, 2H), 1.96 (br, 2H), 1.70-1.50 (m, 4H). MS (DCI/NH₃) m/z413 (M+H)⁺, m/z 430 (M+NH₄)⁺, m/z 447 (M+2NH₄—H)⁺. Anal. calc. forC₁₉H₁₉F₃N₂O₃S: C, 55.33; H, 4.64; N, 6.79. Found: C, 55.53; H, 4.71; N,6.55.

EXAMPLE 2262-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 226A 3-Fluoro-4-(methylthio)benzeneboronic acid

3-Fluoro-4-(methylthio)benzeneboronic acid was prepared according to themethod of Example 1, substituting 4-bromo-2-fluorothioanisole in placeof 4-bromothioanisole.

EXAMPLE 226B 2-Benzyl-4-methoxy-5-bromo-3(2H)-pyridazinone

2-Benzyl-4-methoxy-5-bromo-3(2H)-pyridazinone is prepared according tothe method of Example 83B starting with2-benzyl-4,5-dibromo-3(2H)-pyridazinone, in place of2-(2,2,2-trifluoroethyl)-4,5-dibromo-3(2H)-pyridazinone and substitutingmethanol in place of isopropanol.

EXAMPLE 226C2-Benzyl-4-methoxy-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone

3-Fluoro-4-(methylthio)benzeneboronic acid and2-benzyl-4-methoxy-5-bromo-3(2H)-pyridazinone were coupled according tothe method of Example 83C to provide2-benzyl-4-methoxy-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinoneas a yellow solid (yield: 4.98 g, 91%). ¹H NMR (300 MHz, CDCl₃) ? 7.76(s, 1H), 7.47 (m, 2H), 7.39-7.21 (m, 7H), 5.34 (s, 2H), 4.13 (s, 3H),2.51 (s, 3H). MS (DCI/NH₃) m/z 357 (M+H)⁺, m/z 374 (M+NH₄)⁺.

EXAMPLE 226D 3-Methylbutylmagnesium Bromide

An oven-dried flask containing small pieces of magnesium ribbon (134 mg,5.5 mmol) was charged with diethyl ether (12 mL). 1-Bromo-3-methylbutane600 μL, 5 mmol) was added dropwise, followed by dibromoethane (10 μL).The reaction required heating at gentle reflux before gas evolution wasobserved. The reaction was refluxed for 3 hours and cooled to roomtemperature. The pale gray solution of 3-methylbutylmagnesium bromidewas used in the next reaction.

EXAMPLE 226E2-Benzyl-4-(3-methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone

A solution of2-benzyl-4-methoxy-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone(500 mg, 1.40 mmol), prepared according to the method of Example 226C,in THF (20 mL) was cooled to 78° C. 3-Methylbutylmagnesium bromide (5mL, 1.96 mmol), prepared in Example 226D, was added, dropwise. Uponcompletion of the addition, the reaction mixture was placed in an icebath. After 2.5 hours, the reaction was quenched by adding saturatedammonium chloride solution. The crude reaction mixture was partitionedbetween ethyl acetate and additional ammonium chloride solution. Theorganic layer was washed with brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure to provide a yellowoil (yield: 550 mg, 99%). ¹H NMR (300 MHz, CDCl₃) δ 7.67 (s, 1H), 7.49(m, 2H), 7.39-7.25 (m, 4H), 7.02 (m, 2H), 5.35 (s, 2H), 2.57-2.49 (m,2H), 2.52 (s, 3H), 1.62-1.36 (m, 3H), 0.83 (d, 6H, J=12.0 Hz). MS(DCI/NH₃) m/z 397 (M+H)⁺, m/z 414 (M+NH₄)⁺. MS (DCI/NH₃) m/z 397 (M+H)⁺,m/z 414 (M+NH₄)+

EXAMPLE 226F4-(3-Methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone

2-Benzyl-4-(3-methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone(550 mg, 1.39 mmol), prepared in Example 226E, was debenzylatedaccording to the method of Example 11 to provide4-(3-methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinoneas a pale yellow solid (yield: 375 mg, 88%). ¹H NMR (300 MHz, CDCl₃) δ7.65 (s, 1H), 7.34 (dd, 1H, J=16.2, 16.2 Hz), 7.11-6.98 (m, 2H),2.60-2.50 (m, 0.2H), 2.54 (s, 3H), 1.65-1.37 (m, 3H), 0.83 (d, 6H,J=12.0 Hz). MS (DCI/NH₃) m/z 307 (M+H)⁺, m/z 324 (M+NH4)+MS (DCI/NH₃)m/z 307 (M+H)⁺, m/z 324 (M+NH₄)⁺.

EXAMPLE 226G2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone

4-(3-Methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone(375 mg, 1.23 mmol), prepared in Example 226F, was alkylated accordingto the method of Example 20 to provide2-(2,2,2-trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinoneas a clear oil (yield: 331 mg, 69%). ¹H NMR (300 MHz, CDCl₃) δ 7.67 (s,1H), 7.34 (dd, 1H, J=16.8, 16.8 Hz), 7.11-6.98 (m, 2H), 4.82 (dd, 2H,J=17.4, 17.4 Hz), 2.60-2.51 (m, 2H), 2.53 (s, 3H), 1.61-1.32 (m, 3H),0.85 (d, 6H, J=12.0 Hz). MS (DCI/NH₃) m/z 389 (M+H)⁺, m/z 406 (M+NH₄)⁺.MS (DCI/NH₃) m/z 389 (M+H)⁺, m/z 406 (M+NH₄)⁺.

EXAMPLE 226H2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone

2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone(331 mg, 0.85 mmol), prepared in Example 226G, was oxidized according tothe method of Example 5 using only one equivalent of MCA to provide2-(2,2,2-trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylsulfinyl)phenyl]-3(2H)-pyridazinoneas an off-white solid (yield: 240 mg, 69%). ¹H NMR (300 MHz, CDCl₃) δ8.02 (dd, 1H, J=15.0, 15.0 Hz), 7.67 (s, 1H), 7.37 (dd, 1H, J=17.4, 3.0Hz), 7.11 (dd, 1H, J=18.6, 3.0 Hz), 4.84 (dd, 2H, J=17.4, 17.4 Hz), 2.91(s, 3H), 2.53 (m, 2H), 1.60-1.35 (m, 3H), 0.57 (d, 6H, J=12.0 Hz). MS(DCI/NH₃) m/z 405 (M+H)⁺, m/z 422 (M+NH₄)⁺. MS (DCI/NH₃) m/z 405 (M+H)⁺,m/z 422 (M+NH₄)⁺.

EXAMPLE 226I2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone(240 mg, 0.594 mmol), prepared in Example 226H, was converted to thesulfonamide according to the procedure of Example 68 to provide thetitle compound as a white solid (yield: 109 mg, 44%). mp 153-156° C. ¹HNMR (300 MHz, CDCl₃) δ 8.07 (dd, J=15.0, 15.0 Hz, 1H), 7.74 (s, 1H),7.27-7.19 (m, 2H), 5.14 (br s, 2H), 4.83 (q, J=18.0 Hz, 2H), 2.52 (m,2H), 1.55 (m, 1H), 1.41 (m, 2H), 0.85 (d, J=12.6 Hz, 6H). MS (ESI (−))m/z 420 (M−H)⁻. Anal. calc. for C₁₇H₁₉F₄N₃O₃S: C, 48.45; H, 4.54; N,9.97. Found: C, 48.24; H, 4.56; N, 9.80.

EXAMPLE 2272-(2,2,2-Trifluoroethyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared by adding 1.0 M benzylmagnesium chloridein ether (0.53 mL, 0.53 mmol) to a THF (20 mL) solution of2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(150 mg, 0.41 mmol), prepared according to the method of Example 193E,at 0° C., then allowing the mixture to warm to room temperature over 2hours. After an aqueous work-up, the crude material was purified bycolumn chromatography (silica gel, 65:35 hexanes/ethyl acetate) andcrystallized from ethyl acetate/hexanes to provide white, crystallineproduct (yield: 74 mg, 43%). mp 112-114° C. ¹H NMR (300 MHz, CDCl₃) δ3.12 (s, 3H), 3.94 (s, 2H), 4.85 (q, J=12 Hz, 2H), 6.99 (dd, J=7.5 Hz, 3Hz, 2H), 7.2 (m, 3H), 7.48 (d, J=9 Hz, 2H), 7.72 (s, 1H), 8.06 (d, J=9Hz, 2H). MS (DCI/NH₃) m/z 423 (M+H)⁺. Anal. calc. for C₂₀H₁₇F₃N₂O₃S: C,56.86; H, 4.05; N, 6.63. Found: C, 56.60; H, 4.13; N, 6.57.

EXAMPLE 2282-(4-Fluorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A solution of2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,prepared in Example 194C, (200 mg, 0.51 mmol) in THF (8 ml) was cooledto −78° C. and treated with cyclohexylmagnesium chloride, 2 M solutionin ether (0.31 ml, 0.7 mmol). The reaction mixture was stirred at −78°C. for 2 hours and then was warmed up to room temperature by removingthe cooling bath. Stirred at room temperature for 2 hours water (50 ml)was added to the reaction mixture and extracted with ethyl acetate (50ml). The organic layer was dried over MgSO₄ and concentrated in vacuo.The resulting methyl sulfide compound was purified by flashchromatography (SiO₂, eluting with 9:1 hexanes:ethyl acetate) to providethe desired product (yield: 128 mg, 69%). MS (DCI/NH₃) m/z 395 (M+H)⁺,412 (M+NH₄)⁺.

The methyl sulfide compound, prepared above, (122 mg, 0.3 mmol) inCH₂Cl₂ (10 ml) at 0° C., was treated with CH₃CO₃H (0.3 ml, 1 mmol). Thereaction was complete in 2 hours. The reaction mixture was diluted withCH₂Cl₂ and washed with saturated NaHCO₃ and brine respectively. Theresulting crude residue was purified by flash chromatography (SiO₂,eluting with 1:1 hexanes:ethyl acetate) to provide the desired product(yield: 110 mg, 93%). mp 231-233° C. ¹H NMR (300 MHz, DMSO-d₆) δ 1.1 (m,3H), 1.6 (m, 6H), 2.15 (m, 2H), 7.35 (t, 2H), 7.65 (m, 2H), 7.73 (dd,2H) 7.93 (s, 1H), 8.1 (d, 2H). MS (DCI/NH₃) m/z 427 (M+H)⁺, 444(M+NH₄)⁺. Anal. calc. for C₂₃H₂₃FN₂O₃S.0.75H₂O: C, 64.77; H, 5.44; N,6.57. Found: C, 62.86; H, 5.53; N, 5.78.

EXAMPLE 2292-(4-Fluorophenyl)-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,substituting p-tolylmagnesium bromide in place of cyclohexylmagnesiumchloride (yield: 90 mg, 39%). mp 242-244° C. ¹H NMR (300 MHz, DMSO-d₆) δ2.25 (s, 3H), δ 3.25 (s, 3H), 7.1 (t, 4H), 7.35 (t, 2H), 7.5 (d, J=9 Hz,2H), 7.7 (dd, 2H) 7.9 (d, J=9 Hz, 2H), 8.2 (s, 1H). MS (DCI/NH₃) m/z 435(M+H)⁺, 452 (M+NH₄)⁺. Anal. calc. for C₂₄H₁₉FN₂O₃S.0.5 H₂O: C, 66.34; H,4.41; N, 6.45. Found: C, 64.61; H, 4.57; N, 6.10.

EXAMPLE 2302-(4-Fluorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,substituting benzylmagnesium bromide in place of cyclohexylmagnesiumchloride (yield: 179 mg, 81%). mp 180-182° C. ¹H NMR (300 MHz, DMSO-d₆)δ 3.3 (s, 3H), 7.0 (d, 2H), 7.2 (m, 3H), 7.35 (t, 2H), 7.65 (m, 2H),7.72 (d, 2H) 8.05 (m, 3H). MS (DCI/NH₃) m/z 435 (M+H)⁺, 452 (M+NH₄)⁺.Anal. calc. for C₂₄H₁₉FN₂O₃S.0.5H₂O: C, 66.34; H, 4.41; N, 6.45. Found:C, 66.48; H, 4.17; N, 6.36.

EXAMPLE 2312-(4-Fluorophenyl)-4-(phenylethynyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,substituting phenylacetylene magnesium bromide in place ofcyclohexylmagnesium chloride (yield: 150 mg, 55.5%). mp 203-204° C. ¹HNMR (300 MHz, DMSO-d₆) δ 3.3 (s, 3H), 7.4 (m, 8H), 7.7 (m, 2H), 8.16 (m,4H); 8.35 (s, 1H). MS (DCI/NH₃) m/z 435 (M+H)⁺, 452 (M+NH₄)⁺. Anal.calc. for C₂₅H₁₇FN₂O₃S: C, 67.56; H, 3.86; N, 6.30. Found: C, 67.63; H,3.86; N, 6.30.

EXAMPLE 2322-(3,4-Difluorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,starting with2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(yield: 245 mg, 80%). mp 80-83° C. ¹H NMR (300 MHz, DMSO-d₆) δ 1.1 (m,3H), 1.6 (hi, 6H), 2.15 (m, 2H), 7.5 (m, 1H), 7.6 (m, 2H), 7.7 (d, 2H),7.78 (m, 2H), 7.93 (s, 1H), 8.1 (d, 2H). MS (DCI/NH₃) m/z 445 (M+H)⁺,462 (M+NH₄)⁺. Anal. calc. for C₂₃H₂₂F₂N₂O₃S: C, 62.15; H, 4.99; N, 6.30.Found: C, 62.65; H, 5.25; N, 5.97.

EXAMPLE 2332-(3,4-Difluorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,starting with2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonein place of2-(4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneand substituting benzylmagnesium bromide in place of cyclohexylmagnesiumchloride (yield 206 mg, 66%). mp 166-168° C. ¹H NMR (300 MHz, DMSO-d₆) δ3.3 (s, 3H), 3.9 (s, 2H), 7.0 (d, 2H), 7.2 (m, 3H), 7.6 (m, 2H), 7.72(d, 2H), 7.8 (d, 1H), 8.05 (d, 2H), 8.12 (s, 1H). MS HCl/NH₃) m/z 453(M+H)⁺, 470 (M+NH₄)⁺. Anal. calc. for C₂₄H₁₉F₂N₂O₃S: C, 63.71; H, 4.01;N, 6.19. Found: C, 63.53; H, 4.33; N, 5.76.

EXAMPLE 2342-(3,4-Difluorophenyl)-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,starting with2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonein place of2-(4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneand substituting p-tolylmagnesium bromide in place ofcyclohexylmagnesium chloride (yield: 140 mg, 56%). mp 190-192° C. ¹H NMR(300 MHz, DMSO-d₆) δ 2.28 (s, 2H), δ 3.25 (s, 3H), 7.1 (s, 4H), 7.5 (m,4H), 7.89 (m, 3H), 8.05 (d, 2H), 8.23 (s, 1H). MS (DCI/NH₃) m/z 453(M+H)⁺, 470 (M+NH₄)⁺. Anal. calc. for C₂₄F₂H₁₈N₂O₃S: C, 63.71; H, 4.01;N, 6.19. Found: C, 63.69; H, 4.29; N, 5.96.

EXAMPLE 2352-(3,4-Difluoro-phenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,starting with2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneand substituting 4-fluoro-3-methylbenzenemagnesium bromide in place ofcyclohexylmagnesium chloride (yield: 180 mg, 72.5%). mp 166-168° C. ¹HNMR (300 MHz, DMSO-d₆) δ 2.15 (s, 3H), δ 3.25 (s, 3H), 7.01 (m, 2H),7.25 (d, 1H), 7.6 (m, 4H), 7.9 (m, 3H), 8.26 (s, 2H). MS (DCI/NH₃) m/z471 (M+H)⁺, 488 (M+NH₄)⁺. Anal. calc. for C₂₄F₃H₁₇N₂O₃S: C, 61.27; H,3.64; N, 5.95. Found: C, 61.47; H, 3.84; N, 5.67.

EXAMPLE 2362-(3,4-Difluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-vinyl-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,starting with2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneand substituting vinyl magnesium bromide in place of cyclohexylmagnesiumchloride (yield: 85 mg, 31.8%). ¹H NMR (300 MHz, DMSO-d₆) δ 2.15 (s,3H), δ 3.3 (s, 3H), 5.7 (dd, 1H), 6.4 (dd, 1H), 6.7 (dd, 1H) 7.01 (m,2H), 7.5 (m, 1H), 7.65 (m, 1H), 7.8 (m, 3H), 8.1 (s, 3H). MS (DCI/NH₃)M/Z 389 (M+H)⁺, 406 (M+NH₄)⁺.

EXAMPLE 2372-(3,4-Difluorophenyl)-4-(2-thienyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,starting with2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneand substituting 2-thienylmagnesium bromide in place ofcyclohexylmagnesium chloride (yield: 66 mg, 28%). mp 189-191° C. ¹H NMR(300 MHz, DMSO-d₆) δ 3.3 (s, 3H), 6.95 (m, 2H), 7.55 (m, 1H), 7.7 (m,5H), 7.85 (m, 1H), 8.03 (d, J=9 Hz, 2H), 8.13 (s, 1H). MS (DCI/NH₃) m/z445 (M+H)⁺, 462 (M+NH₄)⁺. Anal. calc. for C₂₁H₁₄F₂N₂O₃S₂: C, 56.75; H,3.17; N, 6.30. Found: C, 56.92, H, 3.92; N, 5.79.

EXAMPLE 2382-(3,4-Difluoro-phenyl)-4-(1-propenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,starting with2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneand substituting methylacetylenemagnesium bromide in place ofcyclohexylmagnesium chloride (yield: 65 mg, 24%). mp 149-150° C. ¹H NMR(300 MHz, DMSO-d₆) δ 2.1 (s, 3H), 3.3 (s, 3H), 7.51 (m, 1H), 7.65 (m,1H), 7.8 (m, 1H), 8.1 (m, 4H); 8.3 (s, 1H). MS (DCI/NH₃) m/z 463M+H)⁺,480 (M+NH₄)⁺. Anal. calc. for C₂₀H₁₄F₂N₂O₃S.0.25H₂O: C, 59.94; H, 3.52;N, 7.00. Found: C, 59.49; H, 3.63; N, 6.34.

EXAMPLE 2392-(3,4-Difluorophenyl)-4-t-butyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,starting with2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneand substituting t-butylmagnesium bromide in place ofcyclohexylmagnesium chloride (yield: 60 mg, 24%). mp 158-161° C. ¹H NMR(300 MHz, DMSO-d₆) δ 1.21, (s, 9H), 3.3 (s, 3H), 7.51 (m, 1H), 7.45 (m,1H), 7.75 (m, 4H), 8.02 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 419 (M+H)⁺,436 (M+NH₄)⁺. Anal. calc. for C₂₁H₂₀F₂N₂O₃S: C, 60.27; H, 4.82; N, 6.69.Found: C, 60.15; H, 5.10; N, 6.39

EXAMPLE 2402-(2,2,2-Trifluoroethyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,starting with2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,prepared in Example 193D, in place of2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,(yield: 120 mg, 53%). mp 215-218° C. ¹H NMR (300 MHz, CDCl₃) δ 1.1 (tt,J=9 Hz, J=4.5 Hz, 2H), 1.25 (tt, J=9 Hz, 4.5 Hz, 1H), 1.49 (d, J=12 Hz,2H), 1.63 (d, J=12 Hz, 1H), 1.75 (dt, J=12 Hz, 3 Hz, 2H), 2.21 (qd, J=9Hz, 4.5 Hz, 2H), 2.51 (tt, J=12 Hz, 3 Hz, 1H), 3.17 (s, 3H), 4.83 (q,J=12 Hz, 2H), 7.49 (d, J=9 Hz, 2H), 7.6 (s, 1H), 8.09 (d, J=9 Hz, 2H).MS (DCI/NH₃) m/z 415 (M+H)⁺. Anal. calc. for C₁₉H₂₁F₃N₂O₃S: C, 55.06; H,5.1; N, 6.75. Found: C, 55.08; H, 5.10; N, 6.70.

EXAMPLE 2412-(3-Chlorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-(3-Chlorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonewas prepared according to the method of Example 228, starting with2-(3-chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,prepared in Example 207C, and substituting 3-fluorobenzylmagnesiumchloride in place of cyclohexylmagnesium chloride to provide the methylsulfide compound.

The methyl sulfide compound was oxidized according to the method ofExample 10 to provide the title compound (yield: 180 mg, 55%). mp142-143° C. ¹H NMR (300 MHz, CDCl₃) δ 3.14 (s, 3H), 3.98 (s, 2H), 6.75(br d, J=9 Hz, 1H), 6.82 (br d, J=9 Hz, 1H), 6.88 (br t, J=9 Hz, 1H),7.15-7.23 (m, 1H), 7.37-7.47 (m, 2H), 7.54 (d, J=9 Hz, 2H), 7.63 (dt,J=9 Hz, 2 Hz, 1H), 7.75 (t, J=2 Hz, 1H), 7.82 (s, 1H), 8.10 (d, J=9 Hz,2H). MS (DCI/NH₃) m/z 469 (M+H)⁺, 486 (M+NH₄)⁺. Anal. calc. forC₂₄H₁₈ClF₂N₂O₃S.0.5H₂O: C, 60.38; H, 3.88; N, 5.87. Found: C, 60.62; H,3.89; N, 5.82.

EXAMPLE 2422-(4-Fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-(4-Fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonewas prepared according to the method of Example 228, starting with2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,prepared in Example 194C, and substituting 3-fluorobenzylmagnesiumchloride in place of cyclohexylmagnesium chloride to provide the methylsulfide compound.

The methyl sulfide compound was oxidized according to the method ofExample 10, to provide the title compound (yield: 450 mg, 66.8%). mp176-178° C. ¹H NMR (300 MHz, CDCl₃) δ 3.14 (s, 3H), 3.95 (s, 2H), 6.75(br d, J=9 Hz, 1H), 6.82 (br d, J=9 Hz, 1H), 6.88 (br t, J=9 Hz, 1H),7.14-7.23 (m, 3H), 7.54 (d, J=9 Hz, 2H), 7.67 (dd, J=9 Hz, 6 Hz, 2H),7.81 (s, 1H), 8.10 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 516 (M+NH₄)⁺. Anal.calc. for C₂₄H₁₉F₂N₂O₅S.H₂O: C, 61.28; H, 4.04; N, 5.96. Found: C,61.24; H, 4.09; N, 5.77.

EXAMPLE 2432-(3,4-Difluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-(3,4-Difluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonewas prepared according to the method of Example 228, starting with2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,and substituting 3-fluorobenzylmagnesium chloride in place ofcyclohexylmagnesium chloride to provide the methyl sulfide compound.

The methyl sulfide compound was oxidized according to the method ofExample 10 to provide the title compound (yield: 390 mg, 68%). mp161-163° C. ¹H NMR (300 MHz, CDCl₃) δ 3.14 (s, 3H), 3.95 (s, 2H), 6.74(br d, J=9 Hz, 1H), 6.82 (br d, J=9 Hz, 1H), 6.89 (br t, J=9 Hz, 1H),7.15-7.33 (m, 2H), 7.48-7.57 (m, 1H), 7.53 (d, J=9 Hz, 2H), 7.59-7.67(m, 1H), 7.83 (s, 1H), 8.10 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 471(M+H)⁺, 488 (M+NH₄)⁺. Anal. calc. for C₂₄H₁₇F₃N₂O₃S.0.5H₂O: C, 60.13; H,3.65; N, 5.85. Found: C, 60.08; H, 3.81; N, 5.54.

EXAMPLE 2442-(3-Chlorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-(3-Chlorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonewas prepared according to the method of Example 228, starting with2-(3-chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,prepared in Example 207C, and substituting4-fluoro-3-methylphenylmagnesium bromide in place of cyclohexylmagnesiumchloride to provide the methyl sulfide compound.

The methyl sulfide compound was oxidized according to the method ofExample 10 to provide the title compound (yield: 620 mg, 57%). mp228-230° C. ¹H NMR (300 MHz, CDCl₃) δ 2.20 (s, 3H), 3.06 (s, 3H),6.83-6.93 (m, 2H), 7.19 (br d, J=9 Hz, 1H), 7.37-7.47 (m, 2H), 7.40 (d,J=9 Hz, 2H), 7.65 (dt, J=7 Hz, 3 Hz, 1H), 7.68 (t, J=3 Hz, 1H), 7.91 (d,J=9 Hz, 2H), 7.98 (s, 1H). MS (DCI/NH₃) m/z 469 (M+H)⁺, 486 (M+N4)⁺.Anal. calc. for C₂₄H₁₈ClFN₂O₃S: C, 61.54; H, 3.85; N, 5.99. Found: C,61.39; H, 3.84; N, 5.82.

EXAMPLE 2452-(4-Fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone

2-(4-Fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonewas prepared according to the method of Example 228, starting with2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,prepared in Example 194C, and substituting4-fluoro-3-methylphenylmagnesium bromide in place of cyclohexylmagnesiumchloride to provide the methyl sulfide compound.

The methyl sulfide compound was oxidized according to the method ofExample 10 to provide the title compound (yield: 590 mg, 74.4%). mp245-247° C. ¹H NMR (300 MHz, CDCl₃) δ 2.01 (s, 3H), 3.07 (s, 3H), 6.87(m, 2H), 7.21 (m, 3H), 7.41 (d, J=9 Hz, 2H), 7.68 (m, 2H), 7.92 (d, J=9Hz, 2H), 7.97 (s, 1H). MS (DCI/NH₃) m/z 453 (M+H)⁺, 470 (M+NH₄)⁺. Anal.calc. for C₂₄H₁₈F₂N₂O₃S.0.5H₂O: C, 62.47; H, 3.90; N, 6.08. Found: C,62.11; H, 4.11; —N, 5.81.

EXAMPLE 2462-(3-Chloro-4-fluorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 246A 2-(3-Chloro-4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone

The title compound is prepared according to the method of Example 194A,substituting 3-chloro-4-fluorophenyl hydrazine.HCl in place of4-fluorophenyl hydrazine.HCl (yield: 9.1 g, 9%). ¹H NMR (300 MHz, CDCl₃)7.22 (d, J=9 Hz, 1H), 7.53-7.58 (m, 1H), 7.73 (dd, J=9 Hz, 3 Hz, 1H),7.94 (s, 1H). MS (DCI/NH₃) m/z 383 (M+H)⁺, 400 (M+NH₄)

EXAMPLE 246B2-(3-Chloro-4-fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone

The title compound is prepared according to the method of Example 194B,substituting 2-(3-chloro-4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinonein place of 2-(4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone (yield:5.6 g, 84%). ¹H NMR (300 MHz, CDCl₃) 4.32 (s, 3H), 7.22-7.30 (m, 1H),7.45-7.55 (m, 1H), 7.64-7.74 (m, 1H), 7.94 (d, J=9 Hz, 1H). MS (DCI/N3)m/z 335 (M+H)⁺, 352 (M+NH₄)⁺.

EXAMPLE 246C2-(3-Chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

The title compound is prepared according to the method of Example 6starting with2-(3-chloro-4-fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone inplace of 2-benzyl-5-methoxy-4-bromo-3(2H)-pyridazinone and substituting4-(methylthio)benzeneboronic acid in place of 4-fluorobenzeneboronicacid (yield: 3.2 g, 63%). ¹H NMR (300 MHz, CDCl₃) δ 2.53 (s, 3H), 4.13(s, 3H), 7.25 (t, J=9 Hz, 1H), 7.35 (d, J=9 Hz, 2H), 7.52 (d, J=9 Hz,2H), 7.55-7.64 (m, 1H), 7.78 (dd, J=9 Hz, 3 Hz, 1H), 7.93 (s, 2H). MS(DCI/NH₃) m/z 377 (M+H)⁺, 394 (M+NH₄)⁺.

EXAMPLE 246D2-(3-Chloro-4-fluorophenyl)-4-cyclohexyl-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

The title compound is prepared starting with2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneby treatment of the methoxy-sulfide compound with cyclohexylmagnesiumchloride according to the method of Example 228 to provide thecyclohexyl sulfide compound.

EXAMPLE 246E2-(3-Chloro-4-fluorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The methyl sulfide compound was oxidized according to the method ofExample 10 to provide the title compound (yield: 150 mg, 53%). mp180-181° C. ¹H NMR (300 MHz, CDCl₃) δ 1.02-1.36 (m, 2H), 1.49-1.68 (m,4H), 1.75 (br d, J=12 Hz, 2H), 2.28 (dq, J=12 Hz, 3 Hz, 2H), 2.57 (tt,J=12 Hz, 3 Hz, 1H), 3.17 (s, 3H), 7.25 (t, J=9 Hz, 1H), 7.53 (d, J=9 Hz,1H), 7.53-7.61 (m, 2H), 7.69 (s, 1H), 7.78 (dd, J=9 Hz, 3 Hz, 1H), 8.12(d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 461 (M+H)⁺, 478 (M+NH₄)⁺. Anal. calc.for C₂₃H₂₂ClFN₂O₃S: C, 60.01; H, 4.78; N, 6.09. Found: C, 59.85; H,4.97; N, 5.79.

EXAMPLE 2472-(3-Chloro-4-fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-(3-Chloro-4-fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonewas prepared according to the method of Example 228, starting with2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4(methylthio)phenyl]-3(2H)-pyridazinone, prepared in Example 246C, andsubstituting 4-fluoro-3-methylphenylmagnesium bromide in place ofcyclohexylrmagnesium chloride to provide the methyl sulfide compound.

The methyl sulfide was oxidized according to the method of Example 10 toprovide the title compound (yield: 118 mg, 53.7%). mp 207-208° C. ¹H NMR(300 MHz, CDCl₃) δ 2.21 (br s, 3H), 3.08 (s, 3H), 6.81-6.93 (m, 2H),7.15-7.30 (m, 2H), 7.41 (d, J=9 Hz, 2H), 7.60-7.68 (m, 1H), 7.85 (dd,J=9 Hz, 3 Hz, 1H), 7.93 (d, J=9 Hz, 2H), 7.99 (s, 1H). MS (DCI/NH₃) m/z487 (M+H)⁺, 504 (M+NH₄)⁺. Anal. calc. for C₂₄H₁₇ClF₂N₂O₃S.0.25H₂O: C,58.75; H, 3.52; N, 5.72. Found: C, 58.74; H, 3.60; N, 5.32.

EXAMPLE 2482-(3-Chloro-4-fluorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-(3-Chloro-4-fluorophenyl)-4-benzyl-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonewas prepared according to the method of Example 228, starting with2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,prepared in Example 246C, and substituting benzylmagnesium chloride inplace of cyclohexylmagnesium chloride to provide the methyl sulfidecompound.

The methyl sulfide was oxidized according to the method of Example 10 toprovide the title compound (yield: 110 mg, 38.4%). mp 164-166° C. ¹H NMR(300 MHz, CDCl₃) δ 3.11 (s, 3H), 3.99 (s, 2H), 7.01-7.06 (m, 2H),7.17-7.28 (m, 4H), 7.53 (d, J=9 Hz, 2H), 7.59-7.66 (m, 1H), 7.81 (s,1H), 7.82 (dd, J=6 Hz, 3 Hz, 1H), 8.09 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z473 (M+H)⁺, 490 (M+NH₄)⁺. Anal. calc. for C₂₄H₁₈ClFN₂O₃S: C, 61.54; H,3.85; N, 5.99. Found: C, 61.40; H, 3.82; N, 5.54.

EXAMPLE 2492-(3-Chloro-4-fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-(3-Chloro-4-fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonewas prepared according to the method of Example 228, starting with2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,prepared in Example 246C, and substituting 3-fluorobenzylmagnesiumchloride in place of cyclohexylmagnesium chloride to provide the methylsulfide compound.

The methyl sulfide was oxidized according to the method of Example 10 toprovide the title compound (yield: 33 mg, 15%). mp 101-103° C. ¹H NMR(300MHz, CDCl₃) δ 3.15 (s, 3H), 3.95 (s, 2H), 6.73 (br d, J=9 Hz, 1H),6.81 (br d, J=9 Hz, 1H), 6.88 (br t, J=9 Hz, 1H), 7.15-7.28 (m, 2H),7.51 (d, J=9 Hz, 2H), 7.53 (ddd, J=9 Hz, 3 Hz, 1.5 Hz, 1H), 7.83 (dd,J=6 Hz, 3 Hz, 1H), 7.83 (s, 1H), 8.10 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z487 (M+H)⁺, 504 (M+NH₄)⁺. Anal. calc. for C₂₄H₁₇ClF₂N₂O₃S: C, 58.75; H,3.52; N, 5.62. Found: C, 58.50; H, 3.65; N, 5.29.

EXAMPLE 2502-(4-Fluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(21)-pyridazinone

2-(4-Fluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonewas prepared according to the method of Example 228, starting with2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,prepared in Example 194C, and substituting3-fluoro-4-methylphenylmagnesium bromide in place of cyclohexylmagnesiumchloride to provide the methyl sulfide compound.

The methyl sulfide was oxidized according to the method of Example 10 toprovide the title compound (yield: 540 mg, 73%). mp 245-248° C. ¹H NMR(300 MHz, CDCl₃) δ 2.22 (br s, 3H), 3.05 (s, 3H), 6.83 (dd, J=9 Hz, 1.5Hz, 1H), 6.96 (dd, J=9 Hz, 1.5 Hz, 1H), 7.06 (t, J=9 Hz, 1H), 7.18 (t,J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 7.65-7.72 (m, 2H), 7.91 (d, J=9 Hz,2H), 7.95 (s, 1H). MS (DCI/NH₃) m/z 452 (M+H)⁺, 470 (M+NH₄)⁺. Anal.calc. for C₂₄H₁₈F₂N₂O₃S: C, 63.86; H, 3.99; N, 6.21. Found: C, 63.49; H,4.13; N, 5.98.

EXAMPLE 2512-(3-Chloro-4-fluorophenyl)-4-(3,5-difluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-(3-Chloro-4-fluorophenyl)-4-(3,5-difluoro-4-methoxyphenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonewas prepared according to the method of Example 228, starting with2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,prepared in Example 246C, and substituting3,5-difluoro-4-methoxyphenylmagnesium bromide in place ofcyclohexylmagnesium chloride to provide the methyl sulfide compound.

The methyl sulfide was oxidized according to the method of Example 10 toprovide the title compound (yield: 590 mg, 65.7%). mp 195-197° C. ¹H NMR(300 MHz, CDCl₃) δ 3.10 (s, 3H), 4.12 (s, 3H), 6.81 (br d, J=9 Hz, 2H),7.27 (t, J=9 Hz, 1H), 7.43 (d, J=9 Hz, 2H), 7.60-7.67 (m, 1H), 7.83 (brd, J=9 Hz, 1H), 7.98 (d, J=9 Hz, 2H), 7.98 (s, 1H). MS (DCI/NH₃) m/z 487(M+H)⁺, 504 (M+NH₄)⁺. Anal. calc. for C₂₄H₁₆ClF₃N₂O₃S.0.5H₂O: C, 54.44;H, 3.12; N, 5.30. Found: C, 54.50; H, 3.12; N, 5.15.

EXAMPLE 2522-(3-Chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-(3-Chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonewas prepared according to the method of Example 228, starting with2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,prepared in Example 246C, and substituting 1-(3-methylbutyl)magnesiumbromide in place of cyclohexylmagnesium chloride to provide the methylsulfide compound.

The methyl sulfide was oxidized according to the method of Example 10 toprovide the title compound (yield: 425 mg, 54.4%). mp 102-104° C. ¹H NMR(300 MHz, CDCl₃) δ 0.85 (d, J—Hz, 6H), 1.41-1.62 (m, 1H), 2.50-2.63 (m,2H), 3.30 (s, 3H), 7.22-7.38 (m, 3H), 7.57-7.64 (m, 1H), 7.72 (br s,1H), 7.80 (br d, J=6 Hz, 1H), 8.15 (t, J=9 Hz, H). MS (DCI/NH₃) m/z 467(M+H)⁺, 484 (M+NH₄)⁺. Anal. calc. for C₂₂H₂₁ClF₂N₂O₃S: C, 56.65; H,4.51; N, 6.01. Found: C, 56.25; H, 4.49; N, 6.06.

EXAMPLE 2532-(4-Fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The sulfide from Example 242,2-(4-fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,was oxidized to the methyl sulfoxide with one equivalent ofmeta-chloroperoxybenzoic acid according to the procedure in Example 69Bto provide the sulfinyl compound.

The sulfoxide was converted to the title sulfonamide according to themethod of Example 68 (yield: 120 mg, 31%). mp 199-202° C. ¹H NMR (300MHz, DMSO-d₆) δ 3.92 (s, 2H), 6.85 (br t, J=9 Hz, 2H), 6.99 (br t, J=9Hz, 1H), 7.26 (q, J=7 Hz, 1H), 7.35 (t, J=9 Hz, 2H), 7.50 (s, 2H),7.62-7.71 (m, 4H), 7.95 (d, J=9 Hz, 2H), 8.11 (s, 1H). MS (DCI/NH₃) m/z454 (M+H)⁺, 47.1 (M+NH₄)⁺. Anal. calc. for C₂₃H₁₇F₂N₃O₃S: C, 60.86; H,3.75; N, 9.27. Found: C, 60.99; H, 3.76; N, 9.02.

EXAMPLE 2542-(3,4-Difluorophenyl)-4-(Phenylethynyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,starting with2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(yield: 245 mg, 80%) and substituting phenylethynylmagnesium bromide inplace of cyclohexylnagnesium chloride (yield: 195 mg, 61%). mp 211-213°C. ¹H NMR (300 MHz, DMSO-d₆) δ 7.46 (m, 5H), 7.65 (m, 2H), 8.18 (t, 4H);8.4 (s, 1H). MS (DCI/NH₃) m/z 463M+H)⁺, 480 (M+NH₄)⁺. Anal. calc. forC₂₅H₁₆F₂N₂O₃S: C, 64.56; H, 3.49; N, 6.06. Found: C, 64.49; H, 3.68; N,5.86.

EXAMPLE 2552-(3,4-Difluorophenyl)-4-(3,4-difluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

3,4-Difluorobenzyl bromide (0.1 ml, 0.8 mmol) in ether (10 ml) wastreated with magnesium turnings (19.4 mg, 0.81 mmol) and the reactionmixture was refluxed for 1 hour. The reaction mixture was cooled andadded to a solution of2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(0.25 g, 0.7 mmol) in THF (10 ml) at −78° C. The reaction mixture wasstirred at room temperature for 18 hours. Water (50 ml) was added to thereaction mixture and extracted with ethyl acetate (50 ml). The organiclayer was dried over MgSO₄ and concentrated in vacuo. The resultingcrude residue was purified by flash chromatography (SiO₂, eluting with9:1 hexanes-ethyl acetate) to provide 120 mg of desired product and somestarting material.

The methylthio compound (120 mg, 0.3 mmol) from above in CH₂Cl₂ (10 ml)at 0° C., was treated with CH₃CO₃H (0.3 ml, 1 mmol). The reaction wascomplete in 2 hours. The reaction mixture was diluted with CH₂Cl₂ andwashed with saturated NaHCO₃ and brine respectively. The resulting cruderesidue was purified by flash chromatography (SiO₂, eluting with 1:1hexanes:ethyl acetate) to provide the desired product (yield: 44 mg,13%). mp 177-179° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.3 (s, 3H), 3.9 (s,2H), 6.85 (m, 1H), 7.15 (m, 1H), 7.25 (m, 2H), 7.6 (m, 7H), 8.15 (m,3H). MS (DCI/NH₃) m/z 489 (M+H)⁺, 506 (M+NH₄)⁺. Anal. calc. forC₂₄H₁₆F₄N₂O₃S.0.25H₂O: C, 59.01; H, 3.30; N, 5.74. Found: C, 58.16; H,3.56; N, 4.51.

EXAMPLE 2562-(3,4-Difluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone

The title compound was prepared according to the method of Example 228,starting with2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(yield: 245 mg, 80%) and substituting 1-bromo-3-methylbutane in place ofcyclohexylmagnesium chloride (yield: 198 mg, 48%). mp 55-58° C. ¹H NMR(300 MHz, DMSO-d₆) δ 0.75 (d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 3.3 (s,3H), 7.51 (m, 1H), 7.65 (m, 1H), 7.75 (d, J=9 Hz, 2H), 7.81 (m, 1H) 8.05(s, 1H), 8.12 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 433 (M+H)⁺, 450(M+NH₄)⁺. Anal. calc. for C₂₂H₂₂F₂N₂O₃S.0.25H₂O: C, 61.10; H, 5.13; N,6.48. Found: C, 61.09; H, 5.23; N, 6.36.

EXAMPLE 2572-(3-Chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228starting with2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonefrom Example 246C in place of2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneand substituting 1-bromo-3-methylbutane in place of cyclohexylmagnesiumchloride (yield: 256 mg, 88%). mp 55-58° C. ¹H NMR (300 MHz, DMSO-d₆) δ0.75 (d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 3.3 (s, 3H), 7.62 (m, 2H),7.75 (d, 2H), 7.93 (dd, 1H), 8.05 (s, 1H), 8.12 (d, J=9 Hz, 2H). MS(DCI/NH₃) m/z 449 (M+H)⁺, 466 (M+NH₄)⁺. Anal. calc. forC₂₂H₂₂FN₂O₃SCl.0.25H₂O: C, 58.86; H, 4.94; N, 6.24. Found: C, 59.23; H,5.12; N, 6.00.

EXAMPLE 2582-(3,4-Difluoro-phenyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,procedure starting with2-(3,4-difluorophenyl)-4-methoxy-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-methoxy-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinoneand substituting 1-bromo-3-methylbutane in place of cyclohexylmagnesiumchloride (yield: 100 mg, 20%). mp 119-121° C. ¹H NMR (300 MHz, DMSO-d₆)δ 0.75 (d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 3.4 (s, 3H), 7.51 (m, 1H),7.8 (m, 2H), 7.81 (m, 2H). MS (DCI/NH₃) m/z 451 (M+H)⁺, 468 (M+NH₄)⁺.Anal. calc. for C₂₂H₂₁F₃N₂O₃S: C, 58.66; H, 4.7; N, 6.22.

EXAMPLE 2592-[4-Fluoro-3-(methylthio)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

To a stirred solution of2-(3,4-difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(315 mg, 0.69 mmol), Example 182, in DMF (10 ml) at room temperature wastreated with sodium thiomethoxide (51 mg, 0.7 mmol). The reactionmixture was stirred at room temperature for 3.15 hours. The reaction waspoured into water (75 ml) and extracted into ethyl acetate. The organiclayer was washed two times with brine, dried over MgSO₄, andconcentrated in vacuo. The resulting crude residue was purified usingflash chromatography (SiO₂, eluting with (15:1 CH₂Cl₂:diethyl ether) toprovide the desired product (yield: 30 mg, 8%). mp 105-107° C. ¹H NMR(300 MHz, DMSO-d₆) δ 2.55 (s, 3H), 3.23 (s, 3H), δ 7.15 (m, 2H), 7.3 (m,2H), 7.55 (m, 5H), 7.9 (d, 2H), 8.25 (s, 1H). MS (DCI/NH₃) m/z 485(M+H)⁺, 502 (M+NH₄)⁺. Anal. calc. for C₂₄H₁₈F₂N₂O₃S₂: C, 59.49; H, 3.74;N, 5.78.

EXAMPLE 2602-Benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethylsulfonyl)Phenyl]-3(2H)-pyridazinoneEXAMPLE 260A2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared starting with2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneand oxidizing the sulfide according to the procedure in example 69B

EXAMPLE 260BBis(4-(5-(2-benzyl-4-(4-fluorophenyl)-3(2H)-pyridazinone)phenyl)disulfide

A heterogeneous solution of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone(1.0 g, 2.39 mmol) in trifluoroacetic anhydride (10 mL, 70.8 mmol) wasrapidly stirred at reflux for 2 hours with a bath temperature of 40-43°C. The reaction solution was cooled to 23° C., concentrated in vacuo,and azeotroped with toluene (2×5-7 mL). The resultant yellow/orange oilwas cooled to 0° C., and methanol/triethylamine (1:1, 6 mL) was slowlyadded, along the interior wall of the reaction vessel with rapidstirring. The bright red-orange solution was stirred for 10 minutes at0° C., the cooling bath removed, and the reaction mixture stirred anadditional 1.5 hours warming to, 23° C. The mixture was cooled back to0° C., and a saturated NH₄Cl solution (200 mL) slowly added followed byenough aqueous 1 M HCl to adjust the solution to pH 1-2. The coolingbath was removed and the solution stirred overnight. The mixture wasextracted with ethyl acetate. The ethyl acetate solution was washed withwater and brine, and concentrated in vacuo. The resultant yellow/brownoil (0.89 g) was a mixture of predominantly the mono-sulfide and desireddi-sulfide. Subsequent rapid stirring of a portion of the crude reactionmixture (360 mg) in benzene (100 mL) with 12 (648 mg, 2.55 mmol) at 23°C. for 30 minutes completed the conversion of the mono-sulfide to thedi-sulfide. (Chem. Pharm. Bull., 1992, 40, 2842) The mixture was treatedwith a 0.1 M Na₂S₂O₃ solution to consume the excess 12. This solutionwas extracted with ethyl acetate, and the ethyl acetate layers driedover MgSO₄, filtered, and concentrated in vacuo. The residue wasdissolved in CH₂Cl₂/hexanes and concentrated in vacuo to provide the ofproduct (yield: 347 mg, 90% for partial conversion). ¹H NMR (300 MHz,CDCl₃) 6-5.38 (s, 4H), 6.91 (dd, J=8.8, 8.8 Hz, 4H) 7.02 (d, j=8.7 Hz,4H), 7.11-7.20 (m, 4H), 7.28-7.39 (m, 10H), 7.54 (dd, J=6.9, 1.5 Hz,4H), 7.83 (s, 2H).

EXAMPLE 260C2-Benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethylthio)phenyl]-3(2H)-pyridazinone

A rapidly stirred mixture ofbis[4-{5-[2-benzyl-4-(4-fluorophenyl)-3(2H)-pyridazinone]}-phenyl]-disulfide(140 mg, 0.181 mmol), potassium trifluoroacetate (55 mg, 0.361 mmol),and sulfolane (1.5 mL) was immersed in a 180° C. pre-heated oil bath.The oil bath was heated to increase the temperature to 210° C., and thereaction flask was promptly removed from the oil bath after 10 minutesfrom the point of first immersion. During the course of the reaction,the mixture changed from colorless and heterogeneous to deep, blood redand homogeneous. After cooling to 23° C., the mixture was diluted withethyl acetate and washed with aqueous 1 M HCl, water, and brine. Theethyl acetate solution was dried over MgSO₄, filtered and concentratedin vacuo. The residue was chromatographed (flash silica gel, ethylacetate/hexanes 1:4) to provide the product (yield: 17 mg, 41%).(Tetrahedron Lett., 1996, 37, 9057) ¹H NMR (300 MHz, CDCl₃) δ 5.41 (s,2H), 6.94 (dd, J=8.2, 8.2 Hz, 2H), 7.11-7.20 (m, 4H), 7.31-7.42 (m, 3H),7.52-7.61 (m, 4H), 7.86 (s, 1H). MS (APCI+) m/z 457 (M+H)⁺ and m/z 474(M+NH₄)⁺.

EXAMPLE 260D2-Benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethylsulfonyl)phenyl]-3(2H)-pyridazinone

A solution of2-benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethylthio)phenyl]-3(2H)-pyridazinone(100 mg, 0.219 mmol), 3-chloroperoxybenzoic acid (380 mg, 1.3 mmol,57-86%), and methylene chloride (5 mL) was brought to reflux at a bathtemperature of 55° C. After 1.75 hours, 3.5 hours, 5 hours, and 6 hours,the reaction was not complete and additional 3-chloroperoxybenzoic acid(380 mg, 1.3 mmol, 57-86%) was added each time. With the reactioncompleted after 7.75 hours, the mixture was cooled to 23° C. andconcentrated in vacuo. The residue was diluted with ethyl acetate andcarefully shaken with a NaHSO₃ solution, 3 times, for several minutes toconsume the excess 3-chloroperoxybenzoic acid. The ethyl acetatesolution was subsequently washed with a saturated Na₂CO₃ solution (3×),water, and brine and dried over MgSO₄, filtered, and concentrated invacuo. The residue was chromatographed (flash silica gel, ethylacetate/methylene chloride/hexanes 1:2:7) to provide of product (yield:93 mg, 87%). (J. Med. Chem., 1990, 33, 2569) mp 80-115° C. ¹H NMR (300MHz, DMSO-d₆) δ 5.36 (s, 2H), 7.11 (dd, J=9.0, 9.0 Hz, 2H), 7.18-7.26(m, 2H), 7.29-7.46 (m, 5H), 7.66 (d, J=8.7 Hz, 2H), 8.10 (d, J=8.7 Hz,2H), 8.18 (s, 1H). MS (APCI+) m/z 489 (M+H)⁺ and m/z 506 (M+NH₄)⁺. Anal.calc. for C₂₄H₁₆F₄N₂O₃S: C, 59.02; H, 3.30; N, 5.74. Found: C, 59.30; H,3.48; N, 5.59.

EXAMPLE 2612-(2,2,2-Trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(150 mg, 0.41 mmol), prepared in Example 193E, and neopentyl alcohol (43mg, 0.49 mmol) were dissolved in DMF (2 mL) and NaH (25 mg, 0.62 mmol,600% in mineral oil) was added with shaking and left overnight. Thereaction mixture was carefully quenched with saturated NH₄Cl solution,diluted with ethyl acetate and extracted with 1 N HCl, twice, thenwater, 3 times, and then dried over MgSO₄. After filtration of thedrying agent and concentration of the filtrate in vacuo, the residue waspurified by chromatography on silica gel (Biotage 40S) eluted with 2:1hexanes-ethyl acetate. The product fractions were combined andevaporated to provide the title compound (yield: 137 mg, 76%). mp145-146° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.76 (s, 9H), 3.28 (s, 3H), 4.06(s, 2H), 5.02 (q, J=9 Hz, 2H), 7.88 (d, J=8 Hz, 2H), 8.04 (d, J=8 Hz,2H), 8.13 (s, 1H). MS (DCI/NH₃) m/z 419 (M+H)⁺, 436 (M+NH₄)⁺. Anal.calc. for C₁₈H₂₁F₃N₂O₄S: C, 51.67; H, 5.06; N, 6.69. Found: C, 51.47; H,5.12; N, 6.48.

EXAMPLE 2622-(2,2,2-Trifluoroethyl)-4-(4-methoxyphenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting 4-methoxyphenol in place of neopentyl alcohol (yield: 130mg, 54%). mp 194-195° C. ¹H NMR (300 MHz, DMSO-d₆) δ 2.24 (s, 3H), 3.26(s, 3H), 5.00 (q, J=9 Hz, 2H), 6.88 (d, J=8 Hz, 2H), 7.09 (d, J=8 Hz,2H), 7.37 (d, J=8 Hz, 2H), 8.03 (d, J=8 Hz, 2H), 8.33 (s, 1H). MS (ESI−)m/z 439 (M−H)⁻. Anal. calc. for C₁₉H₁₇F₃N₂O₄S: C, 54.79; H, 3.91; N,6.39. Found: C, 55.04; H, 4.00; N, 6.11.

EXAMPLE 2632-(2,2,2-Trifluoroethyl)-4-(2-fluoro-5-trifluoromethylphenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting 2-fluoro-5-trifluoromethylphenol in place of neopentylalcohol (yield: 155 mg, 89%). mp 133-135° C. ¹H NMR (300 MHz, DMSO-d₆) δ3.28 (s, 3H), 5.03 (q, J=9 Hz, 2H), 7.10-7.53 (m, 2H), 7.72 (dd, J=1 Hz,7 Hz 1H), 7.92 (d, J=8 Hz, 2H), 8.07 (d, J=8 Hz, 2H), 8.38 (s, 1H). MS(DCI/NH₃) m/z 528 (M+NH₄)⁺. Anal. calc. for C₂₀H₁₃F₇N₂O₄S: C, 47.66; H,3.09; N, 5.05. Found: C, 47.68; H, 2.95; N, 5.16.

EXAMPLE 2642-(2,2,2-Trifluoroethyl)-4-(4-cyanophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting 4-cyanophenyl in place of neopentyl alcohol (yield: 109 mg,71%). mp 179-181° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.26 (s, 3H), 5.02 (q,J=9 Hz, 2H), 7.25 (d, J=9 Hz, 2H), 7.81 (d, J=9 Hz, 2H), 7.86 (d, J=8Hz, 2H), 8.03 (d, J=8 Hz, 2H), 8.37 (s, 1H). MS (DCI/NH₃) m/z 467(M+NH₄)⁺. Anal. calc. for C₂₀H₁₄F₃N₃O₄S: C, 53.45; H, 3.14; N, 9.35.Found: C, 53.19; H, 3.01; N, 9.09.

EXAMPLE 2652-(2,2,2-Trifluoroethyl)-4-(3-pyridyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting 3-hydroxypyridine in place of neopentyl alcohol (yield: 120mg, 69%). mp 191-193° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.26 (s, 3H), 5.01(q, J=9 Hz, 2H), 7.36 (dd, J=3 Hz, 8 Hz, 1H), 7.55 (ddd, J=1 Hz, 3 Hz, 8Hz, 1H), 7.88 (d, J=8 Hz, 2H), 8.04 (d, J=8 Hz, 2H), 8.31 (dd, J=1 Hz, 5Hz, 1H), 8.36 (s, 1H), 8.38 (d, J=3 Hz, 1H). MS (DCI/NH₃) m/z 426(M+H)⁺, 443 (M+NH₄)⁺. Anal. calc. for C₁₈H₁₄F₃N₃O₄S: C, 50.82; H, 3.32;N, 9.88. Found: C, 50.95; H, 3.57; N, 9.71.

EXAMPLE 2662-(2,2,2-Trifluoroethyl)-4-(4-n-propylphenoxy)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting 4-(n-propyl)phenol in place of neopentyl alcohol (yield:147 mg, 77%). mp 152-153° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.87 (t, J=7Hz, 3H), 1.54 (h, J=7 Hz, 2H), 3.25 (s, 3H), 5.00 (q, J=9 Hz, 2H), 6.88(d, J=9 Hz, 2H), 7.09 (d, J=9 Hz, 2H), 7.87 (d, J=8 Hz, 2H), 8.02 (d,J=8 Hz, 2H), 8.32 (s, 1H). MS (DCI/NH₃) m/z 484 (M+H)⁺. Anal. calc. forC₂₂H₂₁F₃N₂O₄S: C, 56.33; H, 4.54; N, 6.01. Found: C, 56.23; H, 4.75; N,5.79.

EXAMPLE 2672-(2,2,2-Trifluoroethyl)-4-[4-(methylsulfonyl)phenoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting 4-(methylsulfonyl)phenol in place of neopentyl alcohol(yield: 115 mg, 56%). mp 212-213° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.21(s, 3H), 3.27 (s, 3H), 5.03 (q, J=9 Hz, 2H), 7.31 (d, J=9 Hz, 2H),7.83-7.89 (m, 4H), 8.04 (d, J=8 Hz, 2H), 8.40 (s, 1H). MS (DCI/NH₃) m/z520 (M+NH₄)⁺. Anal. calc. for C₂₀H₁₇F₃N₂O₆S₂: C, 47.81; H, 3.41; N,5.58. Found: C, 47.92; H, 3.18; N, 5.52.

EXAMPLE 2682-(2,2,2-Trifluoroethyl)-4-(4-phenylphenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting 4-phenylphenol in place of neopentyl alcohol (yield: 105mg, 51%). mp 163-165° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.26 (s, 3H), 5.02(q, J=9 Hz, 2H), 7.10 (d, J=8 Hz, 2H), 7.33 (br t, J=7 Hz, 1H), 7.44 (t,J=7 Hz, 2H), 7.57-7.63 (m, 4H), 7.92 (d, J=8 Hz, 2H), 8.04 (d, J=8 Hz,2H), 8.37 (s, 1H). MS (DCI/H₃) m/z 518 (M+NH₄)⁺. Anal. calc. forC₂₅H₁₉F₃N₂O₄S: C, 60.00; H, 3.83; N, 5.60. Found: C, 60.18; H, 3.66; N,5.52.

EXAMPLE 2692-(2,2,2-Trifluoroethyl)-4-[2-(methylthio)ethoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting 2-(methylthio)ethanol in place of neopentyl alcohol (yield:105 mg, 61%). mp 103-105° C. ¹H NMR (300 MHz, DMSO-d₆) δ 2.01 (s, 3H),2.72 (t, J=7 Hz, 2H), 3.29 (s, 3H), 4.59 (t, J=7 Hz, 2H), 5.03 (q, J=9Hz, 2H), 7.91 (d, J=8 Hz, 2H), 8.04 (d, J=8 Hz, 2H), 8.15 (s, 1H). MS(DCI/NH₃) m/z 423 (M+H)⁺, 440 (M+NH₄)⁺. Anal. calc. for C₁₆H₁₇F₃N₂O₄S₂:C, 45.49; H, 4.06; N, 6.33. Found: C, 45.83; H, 4.11; N, 6.42.

EXAMPLE 2702-(2,2,2-Trifluoroethyl)-4-(phenylmethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting benzyl alcohol in place of neopentyl alcohol (yield: 137mg, 76%) mp 121-123° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.28 (s, 3H), 5.06(q, J=9 Hz, 2H), 5.48 (s, 2H), 7.20-7.25 (m, 2H), 7.27-7.81 (m, 3H),7.76 (d, J=8 Hz, 2H), 7.98 (d, J=8 Hz, 2H), 8.12 (s, 1H). MS (DCI/NH₃)m/z 456 (M+H)⁺. Anal. calc. for C₂₀H₁₇F₃N₂O₄S: C, 54.79; H, 3.91; N,6.39. Found: C, 55.10; H, 3.91; N, 6.13.

EXAMPLE 2712-(2,2,2-Trifluoroethyl)-4-(2-furylmethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting 2-hydroxymethyl)furan in place of neopentyl alcohol (yield:101 mg, 58%). mp 113-115° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.28 (s, 3H),5.07 (q, J=9 Hz, 2H), 5.52 (s, 2H), 6.41 (dd, J=2 Hz, 3 Hz, 1H), 6.45(d, J=4 Hz, 1H), 7.62 (d, J=2 Hz, 1H), 7.69 (d, J=8 Hz, 2H), 7.97 (d,J=8 Hz, 2H), 8.13 (s, 1H). MS (DCI/NH₃) m/z 446 (M+NH₄)⁺. Anal. calc.for C₁₈H₁₅F₃N₂O₅S: C, 50.66; H, 3.80; N, 6.21. Found: C, 51.02; H, 3.71;N, 6.23.

EXAMPLE 2722-(2,2,2-Trifluoroethyl)-4-[2-(3,4-dimethoxyphenyl)ethoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting 2-(3,4-dimethoxyphenyl)ethanol in place of neopentylalcohol (yield: 118 mg, 56%). mp 133-134° C. ¹H NMR (300 MHz, DMSO-d₆) δ2.82 (t, J=7 Hz, 2H), 3.28 (s, 3H), 3.63 (s, 3H), 3.70 (s, 3H), 4.68 (t,J=7 Hz, 2H), 5.01 (q, J=9 Hz, 2H), 6.61 (dd, J=2 Hz, 8 Hz, 1H), 6.74 (d,J=2 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 7.74 (d, J=8 Hz, 2H), 7.93 (d, J=8Hz, 2H), 8.11 (s, 1H). MS (DCI/NH₃) m/z 530 (M+NH₄)⁺. Anal. calc. forC₂₃H₂₃F₃N₂O₆S: C, 53.90; H, 4.52; N, 5.47. Found: C, 53.87; H, 4.48; N,5.45.

EXAMPLE 2732-(2,2,2-Trifluoroethyl)-4-[2-(4-morpholino)ethoxy)]-5-[4-(methylsulfonyl)phenyl]-3(24)pyridazinone

The title compound was prepared according to the method of Example 261,substituting 4-(2-hydroxyethyl)morpholine in place of neopentyl alcohol(yield: 111 mg, 59%). mp 147-148° C. ¹H NMR (300 MHz, DMSO-d₆) δ 2.23(m, 4H), 2.46 (t, J=5 Hz, 2H), 3.28 (s, 3H), 3.40 (m, 4H), 4.60 (t, J=5Hz, 2H), 5.02 (q, J=8 Hz, 2H), 7.96 (d, J=8 Hz, 2H), 8.03 (d, J=8 Hz,2H), 8.17 (s, 1H). MS (DCI/NH₃) m/z 462 (M+H)⁺. Anal. calc. forC₁₉H₂₂F₃N₃O₅S: C, 49.45; H, 4.81; N, 9.11. Found: C, 49.59; H, 4.80; N,8.88.

EXAMPLE 2742-(2,2,2-Trifluoroethyl)-4-[2-(1-piperidinyl)ethoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting 1-(2-hydroxyethyl)piperidine in place of neopentyl alcohol(yield: 103 mg, 55%). mp 117-118° C. ¹H NMR (300 MHz, DMSO-d₆) δ 1.30(br s, 6H), 2.20 (br s, 4H), 2.41 (t, J=4 Hz, 2H), 3.28 (s, 3H), 4.60(t, J=5 Hz, 2H), 5.02 (q, J=9 Hz, 2H), 7.97 (d, J=8 Hz, 2H), 8.03 (d,J=8 Hz, 2H), 8.15 (s, 1H). MS (DCI/N3) m/z 460 (M+H)⁺. Anal. calc. forC₂₀H₂₄F₃N₃O₄S: C, 52.28; H, 5.26; N, 9.15. Found: C, 52.22; H, 5.08; N,8.94.

EXAMPLE 2752-(2,2,2-Trifluoroethyl)-4-[4-(carboxamido)phenoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting 4-hydroxybenzamide in place of neopentyl alcohol (yield: 50mg, 26%). mp>250° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.26 (s, 3H), 5.02 (q,J=8 Hz, 2H), 7.08 (d, J=9 Hz, 2H), 7.30 (s, 1H), 7.82 (d, J=9 Hz, 2H),7.88 (d, J=8 Hz, 2H), 7.92 (s, 1H), 8.03 (d, J=8 Hz, 2H), 8.47 (s, 1H).MS (DCI/NH₃) m/z 468 (M+H)⁺, 485 (M+NH₄)⁺. Anal. calc. forC₂₀H₁₆F₃N₃O₅S: C, 51.39; H, 3.45; N, 8.99. Found: C, 51.31; H, 3.28; N,8.77.

EXAMPLE 2762-(2,2,2-Trifluoroethyl)-4-(1-indanyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting 1-indanol in place of neopentyl alcohol (yield: 84 mg,44%). mp 113-114° C. ¹H NMR (300 MHz, DMSO-d₆) δ 2.07-2.14 (m, 1H),2.22-2.35 (m, 1H), 2.73 (dd, J=5 Hz, 7 Hz, 2H), 3.24 (s, 3H), 5.00-5.22(m, 2H), 6.48 (dd, J=2 Hz, 6 Hz, 1H), 7.12-7.24 (m, 2H), 7.21-7.28 (m,2H), 7.44 (d, J=8 Hz, 2H), 7.87 (d, J=8 Hz, 2H), 8.09 (s, 1H). MS(DCI/NH₃) m/z 482 (M+NH₄)⁺. Anal. calc. for C₂₂H₁₉F₃N₂O₄S: C, 57.19; H,4.48; N, 5.80. Found: C, 57.36; H, 4.30; N, 5.78.

EXAMPLE 2772-(2,2,2-Trifluoroethyl)-4-[4-(acetamido)phenoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting 4-acetamidophenol in place of neopentyl alcohol (yield: 45mg, 23%). mp 215-216° C. ¹H NMR (300 MHz, DMSO-d₆) δ 2.02 (s, 3H), 3.26(s, 3H), 5.02 (q, J=8 Hz, 2H), 6.61-6.65 (m, 1H), 7.17-7.20 (m, 2H),7.34 (br s, 1H), 7.88 (d, J=9 Hz, 2H), 8.03 (d, J=8 Hz, 2H), 8.36 (s,1H), 9.97 (s, 1H). MS (DCI/NH₃) m/z 499 (M+NH₄)⁺. Anal. calc. forC₂₁H₁₉F₃N₃O₅S: C, 52.39; H, 3.77; N, 8.73. Found: C, 52.57; H, 4.02; N,8.37.

EXAMPLE 2782-(2,2,2-Trifluoroethyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting 2-methylpropanol in place of neopentyl alcohol (yield: 111mg, 50%). mp 108-110° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.77 (d, J=6.4 Hz,6H), 1.52 (sept, J=6.4 Hz, 1H), 3.28 (s, 3H), 4.17 (d, J=6 Hz, 2H), 5.02(q, J=9 Hz, 2H), 7.88 (d, J=9 Hz, 2H), 8.04 (d, J=9 Hz, 2H), 8.14 (s,1H). MS (DCI/NH₃) m/z 405 (M+H)⁺, 422 (M+NH₄)⁺. Anal. calc. forC₁₇H₁₉F₃N₂O₄S: C, 50.49; H, 4.74; N, 6.93. Found: C, 50.69; H, 4.89; N,6.75.

EXAMPLE 2792-(2,2,2-Trifluoroethyl)-4-(1-methylcyclopropylmethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting 1-methylcyclopropanemethanol in place of neopentyl alcohol(yield: 360 mg, 75.5%). mp 98-99° C. ¹H NMR (300 MHz, CDCl₃) δ 0.35 (dt,J=40 Hz; 5 Hz, 4H), 0.91 (s, 3H), 3.11 (s, 3H), 4.32 (s, 2H), 4.82 (q,J=8.5 Hz, 2H), 7.80 (d, J=8.5 Hz, 2H), 7.84 (s, 1H), 8.06 (d, J=9 Hz,2H). MS (DCI/NH₃) m/z 417 (M+H)⁺, m/z 434 (M+NH₄)⁺. Anal. calc. forC₁₈H₁₉F₃N₂O₄S: C, 51.92; H, 4.60; N, 6.73. Found: C, 51.87; H, 4.72; N,6.69.

EXAMPLE 2802-(2,2,2-Trifluoroethyl)-4-(3,3-dimethylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 261,substituting 3,3-dimethyl-1-butanol in place of neopentyl alcohol(yield: 270 mg, 67.4%). mp 0.83-85° C. ¹H NMR (300 MHz, CDCl₃) δ 0.88(s, 9H), 1.56 (t, J=8 Hz, 2H), 4.60 (t, J=8 Hz, 2H), 4.83 (q, J=8.5 Hz,2H), 7.73 (d, J=8.5 Hz, 2H), 7.81 (s, 1H), 8.05 (d, J=8.5 Hz, 2H). MS(DCI/NH₃) m/z 433 (M+H)⁺, m/z 450 (M+NH₄)⁺. Anal. calc. forC₁₉H₂₃F₃N₂O₄S: C, 52.77; H, 5.36; N, 6.48. Found: C, 52.95; H, 5.29; N,6.35.

EXAMPLE 2812-(3,4-Difluorophenyl)-4-(4-chlorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A mixture of2-benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (187mg, 0.5 mmol), prepared in Example 78, p-chlorophenol (129 mg, 0.5 mmol)and NaH (60% oil suspension) (40 mg, 1 mmol) in THF (25 mL) was refluxedat 50° C. for 3 hours and then concentrated in vacuo. The residue waspartitioned between water and ethyl acetate. The acetate layer waswashed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was chromatographed (silica gel, 1:1 hexanes-ethyl acetate) toprovide2-benzyl-4-(4-chlorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 200 mg, 82%).

The above derivative was dissolved in toluene (25 mL) and was treatedwith AlBr₃ (400 mg, 1.5 mmol) for 20 minutes at 80° C. The mixture wascooled to room temperature and poured into ice-10% citric acid-ethylacetate. The organic layer was separated, dried over MgSO₄ andconcentrated in vacuo to provide crude desbenzyl derivative. Thiscompound was immediately dissolved in pyridine (50 μL) and was treatedwith 3,4-difluorobromobenzene (0.17 mL, 1.5 mmol), Cu (20 mg) and K₂CO₃(100 mg, 1.5 mmol) at reflux for 16 hours. After the mixture wasconcentrated in vacuo, the residue was dissolved in ethyl acetate andwas washed with water, 10% citric acid and brine. Purification by columnchromatography (silica gel, 1: I hexanes-ethyl acetate) provided thetitle compound (yield: 73 mg, 30%). mp 192-194° C. ¹H NMR (300 MHz,DMSO-dr) δ 3.22 (s, 3H), 7.13 (m, 2H), 7.35 (m, 2H), 7.50 (m, 1H), 7.60(m, 1H), 7.75 (m, 1H), 7.87 (d, J=9 Hz, 2H), 8.05 (d, J=9 Hz, 2H), 8.41(s, 1H). MS (APCI+) m/z 488 (M+H)+ and (APCI−) m/z 523 (M+Cl)⁻.

EXAMPLE 2822-(3,4-Difluorophenyl)-4-(4-bromophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 281,substituting p-bromophenol in place of p-chlorophenol (yield: 54 mg,20%). mp 196-199° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.25 (s, 3H), 7.09 (d,J=9 Hz, 2H), 7.47 (d, J=9 Hz, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.78 (m,1H), 7.89 (d, J=9 Hz, 2H), 8.05 (d, J=9 Hz, 2H), 8.41 (s, 1H). MS(APCI+) m/z 533 (M+H)⁺ and (APCI−) m/z 569 (M+Cl)⁻.

EXAMPLE 2832-(2,2,2-Trifluoroethyl)-4-(cyclopentylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone

To a solution of NaH (26 mg, 1.1 mmol) in acetonitrile (3.0 mL), undernitrogen, was added cyclopentyl mercaptan (120 μL, 1.1 mmol) dropwisevia syringe. The resulting solution was flushed with nitrogen for aperiod of 20 minutes; after which2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone,prepared in Example 193E, (200 mg, 0.52 mmol) was added in one portion.The solution was stirred for an additional 20 minutes at which time, allthe 4-bromo pyridazinone was consumed. The solution was analyzed by TLC(1:1, ethyl acetate-Hex). Water (5 mL) was carefully added and thereaction partitioned between ethyl acetate (125 mL) and saturated saline(50 mL). The organic layer is washed with saturated saline (50 mL),dried over MgSO₄, and concentrated in vacuo. Silica gel chromatography(20% ethyl acetate-80% hexanes) provided a pale yellow solid (yield: 202mg, 83.1%). mp 149-151° C. ¹H NMR (300 MHz, CDCl₃) δ 1.40-1.34 (m, 2H),1.62-1.54 (m, 4H), 1.93-1.88 (m, 2H), 3.13 (s, 3H), 4.40-4.35 (m, 1H),4.85 (q, J=8.2 Hz, 2H), 7.58 (d, J=8.5 Hz, 2H), 7.66 (s, 1H), 8.06 (d,J=8.4 Hz, 2H): MS (DCI/NH₃) m/z 432 (M+H)⁺, (M+NH₄)⁺. Anal. calc. forC₁₈H₁₉F₃N₂O₃S₂: C, 49.99; H, 4.43; N, 6.48. Found: C, 50.15; H, 4.39; N,6.45.

EXAMPLE 2842-(2,2,2-Trifluoroethyl)-4-(1H-1,2,4-triazole-3-ylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 283,substituting 1H-1,2,4-triazole-3-thiol in place of cyclopentyl mercaptan(yield: 164 mg, 93%). mp 197-200° C. ¹H NMR (300 MHz, CDCl₃) δ 3.14 (s,3H), 4.84 (q, J=8.1 Hz, 2H), 7.41 (s, 1H), 7.68 (d, J=6.8 Hz, 2H), 7.83(s, 1H), 8.00 (d, J=7.1 Hz, 2H), 8.05 (s, 1H). MS (DCI/NH₃) m/z 431(M+H)⁺, (M+NH₄)⁺. Anal. calc. for C₁₅H₁₂F₃N₂O₃S₂: C, 41.76; H, 2.80; N,16.23. Found: C, 41.68; H, 2.85; N, 15.99.

EXAMPLE 2852-(2,2,2-Trifluoroethyl)-4-phenylmethylthio-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 283,substituting benzyl mercaptan in place of cyclopentyl mercaptan (yield:141 mg, 76%). mp 108-111° C. ¹H NMR (300 MHz, CDCl₃) δ 3.01 (s, 3H),4.38 (s, 2H), 4.87 (q, J=Hz, 2H), 7.10-7.06 (m, 2H), 7.22-7.20 (m, 5H),7.59 (s, 1H), 7.95 (d, J=8.5 Hz, 2H). MS (DCI/NH₃) m/z 454 (M+H)⁺,(M+NH₄)⁺. Anal. calc. for C₂₀H₁₇F₃N₂O₃S₂, 0.75 EtOAc: C, 53.06; H, 4.45;N, 5.38. Found: C, 53.55; H, 4.16; N, 5.84.

EXAMPLE 2862-(2,2,2-Trifluoroethyl)-4-(4-fluorophenylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 283,substituting 4-fluorophenylmethyl mercaptan in place of cyclopentylmercaptan (yield: 184 mg, 73.5%). mp 182-185° C. ¹H NMR (300 MHz, CDCl₃)δ 3.08 (s, 3H), 4.82 (q, J=8.5 Hz, 2H), 6.87-60.81 (m, 2H), 7.19-7.11(m, 2H), 7.48 (d, J=9.0 Hz, 2H), 7.68 (s, 1H), 7.93 (d, J=8.5 Hz, 2H).MS (DCI/NH₃) m/z 458 (M+H)⁺, (M+NH₄)⁺. Anal. calc. for C₁₉H₁₄F₄N₂O₃S₂:C, 49.78; H, 3.08; N, 6.11. Found: C, 49.89; H, 3.18; N, 5.86

EXAMPLE 2872-(2,2,2-Trifluoroethyl)-4-(cyclohexylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 283,substituting cyclohexyl mercaptan in place of cyclopentyl mercaptan(yield: 189 mg, 78%). mp 165-167° C. ¹H NMR (300 MHz, CDCl₃) δ 1.28-1.17(m, 5H), 1.64-1.56 (m, 3H), 1.82-1.79 (m, 2H), 3.13 (s, 3H), 4.08-4.05(m, 1H), 4.86 (q, J=8.5 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.67 (s, 1H),8.06 (d, J=8.5 Hz, 2H). MS (DCI/NH₃) m/z 446 (M+H)⁺, (M+NH₄)⁺. Anal.calc. for C₁₉H₂₁F₃N₂O₃S₂: C, 51.11; H, 4.74; N, 6.27. Found: C, 51.39H,4.72; N, 5.91.

EXAMPLE 2882-(2,2,2-Trifluoroethyl)-4-(3-chloro-4-fluorophenylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 283,substituting 3-chloro-4-fluorothiophenol in place of cyclopentylmercaptan (yield: 190 mg, 65%). mp 142-145° C. ¹H NMR (300 MHz, CDCl₃) δ3.18 (s, 3H), 4.85 (q, J=8.4 Hz, 2H), 6.96 (ov. t, J=8.5 Hz, 1H),7.14-7.10 (m, 1H), 7.18 (dd, J=2.1, 6.5 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H),7.77 (s, 1H), 7.96 (d, J=8.0 Hz, 2H). MS (CI) m/z 493 (M+1)⁺, (M+NH₄)⁺.Anal. calc. for C₁₉H₁₃ClF₄N₂O₃S₂.0.25 C₆H₆.H₂O: C, 47.36; H, 2.92; N,5.41. Found: C, 47.88; H, 2.95; N, 5.24.

EXAMPLE 2892-(2,2,2-Trifluoroethyl)-4-(2,2,2-trifluoroethylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 283,substituting 2,2,2-trifluoroethyl mercaptan in place of cyclopentylmercaptan (yield: 175 mg, 66%). mp 155-158° C. ¹H NMR (300 MHz, CDCl₃) δ3.14 (s, 3H), 3.98 (q, J=9.8 Hz, 2H), 4.86 (q, J=8.1 Hz, 2H), 7.58 (d,J=8.4 Hz, 2H), 7.75 (s, 1H), 8.10 (d, J=8.4 Hz, 2H). MS (DCI/NH₃) m/z446 (M+H)⁺, (M+NH₄)⁺. Anal. calc. for C₁₅H₁₂F₆N₂O₃S₂: C, 40.36; H, 2.71;N, 6.28. Found: C, 40.50; H, 2.72; N, 6.01.

EXAMPLE 2902-(2,2,2-Trifluoroethyl)-4-(tert-butylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 283,substituting tert-butyl mercaptan in place of cyclopentyl mercaptan(yield: 212 mg, 85%). mp 186-189° C. ¹H NMR (300 MHz, CDCl₃) δ 1.25 (s,9H), 3.13 (s, 3H), 4.87 (q, J=8.1 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.67(s, 1H), 8.05 (d, J=8.1 Hz, 2H). MS (ESI) m/z 420 (M+H)⁺, (M+Na)⁺. Anal.calc. for C₁₇H₁₉F₃N₂O₃S₂: C, 48.56; H, 4.55; N, 6.66. Found: C, 50.15;H, 4.39; N, 6.45.

EXAMPLE 2912-(2,2,2-Trifluoroethyl)-4-(4-acetamidophenylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 283,substituting 4-acetamidothiophenol in place of cyclopentyl mercaptan(yield: 100 mg, 37%). mp 191-193° C. ¹H NMR (300 MHz, CDCl₃) δ 2.16 (s,3H), 3.08 (s, 3H), 4.83 (q, J=8.2 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 7.19(d, J=8.8 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 7.58 (s, 1H), 7.78 (d, J=8.1Hz, 2H). MS (CI) m/z 497 (M+H)⁺, (M+NH₄)⁺. Anal. calc. forC₂₁H₁₈F₃N₃O₄S₂.0.25H₂O, 0.25 C₆H₆: C, 52.83; H, 4.06; N, 7.70. Found: C,52.97; H, 3.85; N, 7.65.

EXAMPLE 2922-(2,2,2-Trifluoroethyl)-4-(2-propylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 283,substituting isopropyl mercaptan in place of cyclopentyl mercaptan(yield: 180 mg, 81%). mp 165-167° C. ¹H NMR (300 MHz, CDCl₃) δ 1.17 (d,J=6.8 Hz, 6H), 3.13 (s, 3H), 4.33 (p, J=6.8 Hz, 1H), 4.86 (q, J=8.5 Hz,2H), 6.59 (d, J=8.5 Hz, 2H), 7.68 (s, 1H), 8.07 (d, J=8.1 Hz, 2H). MS(DCI/NH₃) m/z 406 (M+H)⁺, (M+NH₄)⁺. Anal. calc. for C₁₆H₁₇F₃N₂O₃S₂,0.75H₂O: C, 45.76; H, 4.4; N, 6.67. Found: C, 45.91; H, 3.98; N, 6.46.

EXAMPLE 2932-(2,2,2-Trifluoroethyl)-4-(2-methylprop-1-ylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 283substituting 2-methyl-1-propyl mercaptan in place of cyclopentylmercaptan (yield: 100 mg, 83%). mp 135-138° C. ¹H NMR (300 MHz, CDCl₃) δ0.87 (d, J=6.4 Hz, 6H), 1.67-1.60 (m, 1H), 3.00 (d, J=6.7 Hz, 2H), 3.14(s, 3H), 4.84 (q, J=8.5 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.67 (s, 1H),8.08 (d, J=8.5 Hz, 2H). MS (DCI/NH₃) m/z 420 (M+H)⁺, (M+NH₄)⁺. Anal.calc. for C₁₇H₁₉F₃N₂O₃S₂: C, 48.56; H, 4.55; N, 6.66. Found: C, 47.86;H, 4.57; N, 6.51.

EXAMPLE 2942-(2,2,2-Trifluoroethyl)-4-amino-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone,prepared according to Example 193E, (500 mg, 1.36 mmol) was dissolved inDMF (10 mL) and treated with NaN₃ (100 mg, 1.5 mmol). After 2 hours atroom temperature, the reaction was diluted with ethyl acetate and washedwith water, 4 times, and dried over MgSO₄. After filtration of thedrying agent and concentration of the filtrate in vacuo, the residue waspurified by chromatography on silica gel (Biotage 40S) eluted with 2:1hexanes-ethyl acetate. The product fractions were combined andevaporated to provide the azido intermediate,2-(2,2,2-Trifluoroethyl)-4-azido-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 481 mg, 95%).

The 4-azido-compound above (39 mg, 0.105 mmol) was dissolved in THF (3mL) and MeOH (2 mL) and treated with excess NaBH₄. After 15 minutes, thereaction was quenched with saturated NH₄Cl solution and the product wasextracted into ethyl acetate. The organic layer was washed with water, 3times, and dried over MgSO₄. Filtration of the drying agent andevaporation of the solvent provided the title compound (yield: 26 mg,71%). mp>260° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.26 (s, 3H), 4.93 (q, J=9Hz, 2H), 6.71 (s, 2H), 7.72 (s, 1H), 7.76 (d, J=8 Hz, 2H), 8.02 (d, J=8Hz, 2H). MS (ESI−) m/z 346 (M−H)⁻. Anal. calc. for C₁₃H₁₂F₃N₃O₃S: C,44.96; H, 3.48; N, 12.10. Found: C, 44.59; H, 3.52; N, 11.93.

EXAMPLE 2952-(2,2,2-Trifluoroethyl)-4-(3-methoxypropylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A solution of2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(200 mg, 0.546 mmol), prepared according to the method of Example 193E,and 3-methoxypropylamine (145 mg, 1.64 mmol) in pyridine (4 mL) washeated at 100° C. for 16 hours. The reaction mixture was cooled to roomtemperature, mixed with silica gel (2 g), and the solvent removed underreduced pressure. The adsorbed silica gel was layered over anExtract-Clean Cartridge® (Alltech, packing: 10 g silica gel) and thecartridge eluted with a hexanes/acetone step gradient consisting of 60mL of each of the following mixtures: hexanes, 8:1 hexanes/acetone, 4:1,2:1, and 1:1. Fractions containing desired product were combined,concentrated, and further purified using HPLC (Technikrom Kromasil 60-5sil silica column, 20 mm×25 cm). The column was eluted with a lineargradient consisting of 30% ethyl acetate/hexanes to 100% ethyl acetateat 10 mL/min over 50 minutes. Fractions containing product were combinedand concentrated under reduced pressure to provide the product asoff-white crystals (yield: 215 mg, 95%). mp 110-113° C. ¹H NMR (300 MHz,CDCl₃) δ 8.02 (d, J=18.0 Hz, 2H), 7.55 (d, 2H, J=18.0 Hz), 7.48 (s, 1H),6.57 (br t, 1H, J=9.0 Hz), 4.81 (q, J=17.4 Hz, 2H), 3.33 (t, J=12.0 Hz,2H), 3.28 (s, 3H), 3.12 (s, 3H), 2.76 (dt, J=12.0, 12.0 Hz, 2H), 1.65(tt, J=12.0, 12.0, Hz, 2H). MS (DCI/NH₃) m/z 420 (M+H)⁺, m/z 437[M+NH₄]⁺. Anal. calc. for C₁₇H₂₀F₃N₃O₄S: C, 48.68; H, 4.81; N, 10.02.Found: C, 48.74; H, 4.69; N, 9.84.

EXAMPLE 2962-(2,2,2-Trifluoroethyl)-4-(cyclopentylamino)-5-[4(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 295,substituting cyclopentylamine in place of 3-methoxypropylamine toprovide brown crystals (yield: 195 mg, 86%). mp 134-139° C. ¹H NMR (300MHz, CDCl₃) δ 8.03 (d, J=18.0 Hz, 2H), 7.56 (d, J=18.0 Hz, 2H), 7.45 (s,1H), 6.12 (br d, J=16.8 Hz, 1H), 4.79 (q, J=17.4 Hz, 2H), 3.33 (br m,1H), 3.12 (s, 3H), 1.64-1.23 (br m, 8H). MS (DCI/NH₃) m/z 416 (M+H)⁺,m/z 433 (M+NH₄)⁺. Anal. calc. for C₁₈H₂₀F₃N₃O₃S: C, 52.04; H, 4.85; N,10.11. Found: C, 52.40; H, 4.93; N, 10.03.

EXAMPLE 2972-(2,2,2-Trifluoroethyl)-4-(cyclobutylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 295,substituting Cyclobutylamide in place of 3-methoxypropylamine to providean off-white solid (yield: 206 mg, 94%). mp 169-172° C. ¹H NMR (300 MHz,CDCl₃) δ 8.03 (d, J=17.4 Hz, 2H), 7.54 (d, J=17.4 Hz, 2H), 7.45 (5, 1H),6.28 (br d, J=16.2 Hz, 1H), 4.81 (q, J=17.4 Hz, 2H), 3.42 (m, 1H), 3.13(s, 3H), 1.79 (m, 4H), 1.64 (m, 1H), 1.39 (m, 1H). MS (DCI/NH₃) M/Z 402(M+H)⁺, m/z 419 (M+NH₄)⁺. Anal calc. for C₁₇H₁₈F₃N₃O₃S.0.25 CH₃COCH₃: C,51.25; H, 4.72; N, 10.10; found: C, 51.38; H, 4.68; N, 10.25.

EXAMPLE 2982-(2,2,2-Trifluoroethyl)-4-(3,4-dimethoxyphenethylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 295,substituting

3,4-dimethoxyphenethylamine in place of 3-methoxypropylamine to providean off-white solid (yield: 206 mg, 94%). mp 163-165° C. ¹H NMR (300 MHz,CDCl₃) δ 8.02 (d, J=18.0 Hz, 2H), 7.52 (d, J=18.0 Hz, 2H), 7.45 (s, 1H),6.75 (d, J=16.2 Hz, 1H), 6.50 (m, 2H), 6.16 (br d, J=11.4 Hz, 1H), 4.79(q, J=17.4 Hz, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.11 (s, 3H), 2.91 (dt,J=12.6, 12.6 Hz, 2H), 2.60 (t, J=13.8 Hz, 2H). MS (DCI/NH₃) m/z 529(M+NH₄)⁺. Anal. calc. for C₂₃H₂₄F₃N₃O₅S: C, 54.01; H, 4.73; N, 8.21.Found: C, 54.30; H, 4.69; N, 8.16.

EXAMPLE 2992-(2,2,2-Trifluoroethyl)-4-(cyclohexylamino)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 295substituting cyclohexylamine in place of 3-methoxypropylamine to providean off-white solid (yield: 103 mg, 42%). ¹H NMR (300 MHz, CDCl₃) δ 8.04(d, J=18.0 Hz, 2H), 7.58 (d, J=18.0 Hz, 2H), 7.44 (s, 1H), 6.06 (br d,J=18.6 Hz, 1H), 4.81 (q, J=18.0 Hz, 2H), 3.11 (s, 3H), 2.70 (m, 1H),1.66-1.48 (m, 4H), 1.42 (m, 1H), 1.07 (m, 3H), 0.76 (m, 2H). MS(DCI/NH₃) m/z 430 (M+H)⁺, m/z 447 (M+NH₄)⁺. Anal. calc. forC₁₉H₂₂F₃N₃O₃S: C, 53.14; H, 5.16; N, 9.78. Found: C, 52.86; H, 5.06; N,9.52.

EXAMPLE 3002-(2,2,2-Trifluoroethyl)-4-[2-(1-piperidinyl)ethylamino]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 295,substituting 2-(1-piperidinyl)ethylamine in place of3-methoxypropylamine to provide an off-white solid (yield: 210 mg, 84%).¹H NMR (300 MHz, CDCl₃) δ 8.02 (d, J=18.0 Hz, 2H), 7.56 (d, J=18.0 Hz,2H), 7.49 (s, 1H), 6.91 (br, 1H), 4.82 (q, J=18.0 Hz, 2H), 3.13 (s, 3H),2.64 (br, 2H), 2.32 (br, 4H), 1.58 (br, 6H), 1.42 (br, 2H). MS (DCI/NH₃)m/z 459 (M+H)⁺. Anal. calc. for C₁₉H₂₂F₃N₃O₃S: C, 52.39; H, 5.50; N,12.22. Found: C, 52.64; H, 5.59; N, 12.00.

EXAMPLE 3012-(2,2,2-Trifluoroethyl)-4-(2-tetrahydrofurfurylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 295,substituting tetrahydrofurfurylamine in place of 3-methoxypropylamine toprovide an off-white solid (yield: 150 mg, 64%). mp 128-129° C. ¹H. NMR(300 MHz, CDCl₃) δ 8.03 (d, J=18.0 Hz, 2H), 7.56 (d, J=18.0 Hz, 2H),7.47 (s, 1H), 6.48 (br t, J=9.0 Hz, 1H), 4.81 (q, J=18.0 Hz, 2H), 3.84(m, 2H), 3.72 (m, 1H), 3.12 (s, 3H), 2.83 (m, 1H), 2.64 (m, 1H), 1.84(m, 3H), 1.34 (m, 1H). MS (DCI/NH₃) m/z 432 (M+H)⁺, m/z 449 (M+NH₄)⁺.Anal. calc. for C₁₈H₂₀F₃N₃O₃S: C, 50.11; H, 4.67; N, 9.74. Found: C,50.25; H, 4.68; N, 9.68.

EXAMPLE 3022-(2,2,2-Trifluoroethyl)-4-(cyclopropylmethylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 295,substituting cyclopropylmethylamine in place of 3-methoxypropylamine toprovide an off-white solid (yield: 130 mg, 59%). mp 145-146° C. ¹H NMR(300 MHz, CDCl₃) δ 8.01 (d, J=18.0 Hz, 2H), 7.53 (d, J=18.0 Hz, 2H),7.48 (s, 1H), 6.20 (br, 1H), 4.82 (q, J=18.0 Hz, 2H), 3.12 (s, 3H), 2.45(br d, J=13.2 Hz, 2H), 0.88 (m, 1H), 0.51 (m, 2H), 0.10 (m, 2H). MS(DCI/NH₃) m/z 402 (M+H)⁺, m/z 419 (M+NH₄)⁺. Anal. calc. forC₁₇H₁₈F₃N₃O₃S: C, 50.87; H, 4.52; N, 10.47. Found: C, 51.00; H, 4.52; N,10.44.

EXAMPLE 3032-(2,2,2-Trifluoroethyl)-4-(2,3-dihydro-1H-inden-1-ylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 295,substituting 1-indanylamine in place of 3-methoxypropylamine to providean off-white solid (yield: 82 mg, 32%). mp 155-158° C. ¹H NMR (300 MHz,CDCl₃) δ 8.04 (d, J=18.0 Hz, 2H), 7.68 (d, J=18.0 Hz, 2H), 7.49 (s, 1H),7.27-7.14 (m, 4H), 6.30 (br d, J=18.0 Hz, 1H), 4.81 (q, J=18.0 Hz, 2H),4.57 (m, 1H), 3.09 (s, 3H), 2.89 (m, 1H), 2.60 (m, 1H), 1.85 (m, 1H),1.68 (m, 1H). MS (ESI (−) m/z 462 (M−H)⁻. Anal. calc. for C₂₂H₂₀F₃N₃O₃S:C, 57.01; H, 4.35; N, 9.07. Found: C, 57.30; H, 4.45; N, 8.86.

EXAMPLE 3042-(2,2,2-Trifluoroethyl)-4-(1-piperidinyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 295,substituting piperidine in place of 3-methoxypropylamine to provide anoff-white solid (yield: 180 mg, 79%). mp 160-161° C. ¹H NMR (300 MHz,CDCl₃) δ 8.04 (d, J=18.0 Hz, 2H), 7.58 (s, 1H), 7.46 (d, J=18.0 Hz, 2H),4.80 (q, J=18.0 Hz, 2H), 3.13 (s, 3H), 2.96 (m, 4H), 1.65-1.52 (m, 6H).MS (DCI/NH₃) m/z 416 (M+H)⁺. Anal. calc. for C₁₈H₂₀F₃N₃O₃S.H₂O: C,52.04; H, 4.85; N, 10.11. Found: C, 52.21; H, 5.02; N, 9.75.

EXAMPLE 3052-(2,2,2-Trifluoroethyl)-4-(3-hydroxypropylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 295,substituting 3-hydroxypropylamine in place of 3-methoxypropylamine toprovide a white solid (yield: 109.6 mg, 50%). mp 152-154° C. ¹H NMR (300MHz, CDCl₃) δ 8.02 (d, J=18.0 Hz, 2H), 7.56 (d, J=18.0 Hz, 2H), 7.48 (s,1H), 6.48 (br, 1H), 4.79 (q, J=17.4 Hz, 2H), 3.63 (t, J=12.0 Hz, 2H),3.12 (s, 3H), 2.81 (dt, J=12.0, 12.0 Hz, 2H), 1.65 (tt, J=12.0, 12.0 Hz,2H). MS (DCI/NH₃) m/z 406 (M+H)⁺, m/z 423 (M+NH₄)⁺. Anal. calc. forC₁₆H₁₈F₃N₃O₄S: C, 47.41; H, 4.48; N, 10.37. Found: C, 47.53; H, 4.33; N,10.27.

EXAMPLE 3062-(2,2,2-Trifluoroethyl)-4-[3-(1H-imidazol-1-yl)propylamino]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 295,substituting 1-(3-aminopropyl)imidazole in place of3-methoxypropylamine. The reaction mixture was concentrated to drynessand the residue purified using RP-HPLC (Rainin Dynamax C-18 column, 60 Åpore size, 21.4 mm i.d.). The column was eluted with a linear gradientconsisting of 20% acetonitrile (containing 0.1% TFA)/80% water(containing 0.1% TFA) to 100% acetonitrile (containing 0.1% TFA) at 15mL/min over 70 minutes. The peak corresponding to the title product wascollected and lyophilized to provide a tan hygroscopic foam (yield: 70.2mg, 28%). ¹H NMR (300 MHz, DMSO) δ 8.95 (br s, 1H), 7.97 (d, J=16.8 Hz,2H), 7.66 (d, J=16.2 Hz, 2H), 7.61 (s, 1H), 7.58 (d, J=15.0 Hz, 2H),6.99 (br t, 1H, J=13.2 Hz), 4.97 (dt, J=18.0, 18.0 Hz, 2H), 3.97 (t,J=13.2 Hz, 2H), 3.28 (s, 3H), 2.69 (m, 2H), 1.81 (tt, J=13.2, 13.2 Hz,2H). MS (DCI/NH₃) m/z 456 (M+H)⁺. Anal. calc. for C₁₉H₂₀F₃N₅O₃S.1.4CF₃COOH: C, 42.57; H, 3.51; N, 11.39. Found: C, 42.78; H, 3.58; N,11.24.

EXAMPLE 3072-(2,2,2-Trifluoroethyl)-4-(2R-hydroxypropylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of +Example 295,substituting (R)-(−)-2-propanolamine in place of 3-methoxypropylamine toprovide an off-white solid (yield: 109.6 mg, 50%). M.p.=140-142° C. ¹HNMR (300 MHz, CDCl₃) δ 8.04 (d, J=18.0 Hz, 2H), 7.56 (d, J=18.0 Hz, 2H),7.49 (s, 1H), 6.42 (br, 1H), 4.79 (m, 2H), 3.80 (m, 1H), 3.12 (s, 3H),2.68 (m, 2H), 1.02 (d, J=12.0 Hz, 3H). MS (DCI/NH₃) m/z 406 (M+H)⁺, m/z423 (M+NH₄)⁺. Anal. calc. for C₁₆H₁₈F₃N₃O₄S: C, 47.41; H, 4.48; N,10.37. Found: C, 47.56; H, 4.41; N, 10.25.

EXAMPLE 3082-(2,2,2-Trifluoroethyl)-4-(2-cyanoethylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 295,substituting

2-cyanoethylamine in place of 3-methoxypropylamine to provide anoff-white solid (yield: 27 mg, 12%). mp 172-174° C. ¹H NMR (300 MHz,CDCl₃) δ 8.09 (d, J=18.0 Hz, 2H), 7.63 (d, J=18.0 Hz, 2H), 7.51 (s, 1H),6.08 (br t, 1H), 4.87 (q, J=18.0 Hz, 2H), 3.17 (dt, J=13.2, 13.2 Hz,2H), 3.13 (s, 3H), 2.39 (t, J=13.2 Hz, 2H). MS (DCI/NH₃) m/z 418(M+NH₄)⁺. Anal. calc. for C₁₆H₁₅F₃N₄O₃S: C, 48.00; H, 3.78; N, 13.99.Found: C, 48.28; H, 3.77; N, 13:80.

EXAMPLE 3092-(2,2,2-Trifluoroethyl)-4-(4-cyanoanilino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A suspension of2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(300 mg, 0.820 mmol), prepared according to the method of Example 193E,4-aminobenzonitrile (290 mg, 2.46 mmol), and silver oxide (760 mg, 3.28mmol) in pyridine (1.5 mL) was stirred at 80° C. for 24 hours. Thereaction was cooled to room temperature, adsorbed onto silica gel (2 g)and solvent removed under reduced pressure. The adsorbed silica gel waslayered over an Extract-Clean Cartridge® (Alltech, packing: 10 g silicagel) and the cartridge eluted with a hexanes/acetone step gradientconsisting of 60 mL of each of the following mixtures: hexanes, 8:1hexanes/acetone, 4:1, 2:1, and 1:1. Fractions containing desired productwere combined, concentrated, and further purified using HPLC (TechnikromKromasil 60-5 sil column, 20 mm×25 cm). The column was eluted with alinear gradient consisting of 30% ethyl acetate/hexanes to 100% ethylacetate at 10 mL/min over 50 minutes. Fractions containing product werecombined and concentrated under reduced pressure to provide the productas a tan solid (yield: 149.9 mg, 41%). mp>230° C. ¹H NMR (300 MHz, DMSO)δ 9.49 (s, 1H), 8.00 (s, 1H), 7.69 (d, J=17.4 Hz, 2H), 7.43 (d, J=16.8Hz, 2H), 7.32 (d, J=18.0 Hz, 2H), 6.78 (d, J=18.0 Hz, 2H), 5.06 (q,J=18.0 Hz, 2H), 3.13 (s, 3H), 2.68 (m, 2H), 1.02 (d, J=12.0 Hz, 3H). MS(DCI/NH₃) m/z 466 (M+NH₄)⁺. Anal. calc. for C₂₀H₁₅F₃N₄O₃S: C, 53.57; H,3.37; N, 12.49. Found: C, 53.47; H, 3.49; N, 12.35.

EXAMPLE 3102-(2,2,2-Trifluoroethyl)-4-[3-methoxy-5-(trifluoromethyl)anilino]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 309,substituting 3-methoxy-5-(trifluoromethyl)aniline in place of4-aminobenzonitrile to provide a brown solid (yield: 226.5 mg, 80%). mp206-208° C. ¹H NMR (300 MHz, CDCl₃) δ 7.90 (s, 1H), 7.77 (s, 1H), 7.71(d, J=18.0 Hz, 2H), 7.28 (d, J=17.4 Hz, 2H), 6.61 (br s, 1H), 6.46 (brs, 1H), 6.3-1 (br s, 1H), 4.90 (q, J=17.4 Hz, 2H), 3.72 (s, 3H), 2.94(s, 3H). MS (DCI/NH₃) m/z 539 (M+NH₄)⁺. Anal. calc. for C₂₁H₁₇F₆N₃O₄S:C, 48.37; H, 3.29; N, 8.06. Found: C, 48.60; H, 3.33; N, 7.94.

EXAMPLE 3112-(2,2,2-Trifluoroethyl)-4-anilino-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 309,substituting aniline in place of 4-aminobenzonitrile to provide a tansolid (yield: 90 mg, 53%). mp 154-156° C. ¹H NMR (300 MHz, CDCl₃) δ 7.89(br s, 1H), 7.72 (s, 1H), 7.62 (d, J=18.0 Hz, 2H), 7.19 (d, J=18.0 Hz,2H), 7.96-7.82 (m, 3H), 6.61 (d, J=14.4 Hz, 2H), 4.90 (q, J=18.0 Hz,2H), 2.94 (s, 3H). MS (DCI/NH₃) m/z 424 (M+H)⁺, m/z 441 (M+NH₄)⁺. Anal.calc. for C₁₉H₁₆F₃N₃O₃S: C, 53.90; H, 3.81; N, 9.92. Found: C, 53.87; H,3.73; N, 9.89.

EXAMPLE 3122-(2,2,2-Trifluoroethyl)-4-(2,5-dimethoxyphenylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 309,substituting 2,5-dimethoxyaniline in place of 4-aminobenzonitrile toprovide a tan solid (yield: 140 mg, 53%). mp 95-96° C. ¹H NMR (300 MHz,CDCl₃) δ 7.78 (br s, 1H), 7.72 (s, 1H), 7.63 (d, J=18.0 Hz, 2H), 7.18(d, J=18.0 Hz, 2H), 6.54 (d, J=18.0 Hz, 1H), 6.38 (dd, J=6.0, 18.0 Hz,1H), 4.89 (q, J=18.0 Hz, 2H), 3.73 (s, 3H), 3.47 (s, 3H), 2.96 (s, 3H).MS (DCI/NH₃) m/z 484 (M+H)⁺, m/z 501 (M+NH₄)⁺. Anal. calc. forC₂₁H₂₀F₃N₃O₅S: C, 52.17; H, 4.17; N, 8.69. Found: C, 52.47; H, 4.17; N,8.43.

EXAMPLE 3132-(2,2,2-Trifluoroethyl)-4-(3-fluoroanilino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 309,substituting 3-fluoroaniline in place of 4-aminobenzonitrile to providea tan solid (yield: 151.3 mg, 42%). mp 156-158° C. ¹H NMR (300 MHz,DMSO) δ 9.18 (s, 1H), 7.91 (s, 1H), 7.62 (d, J=17.4 Hz, 2H), 7.36 (d,J=17.4 Hz, 2H), 6.88 (dd, J=15.0, 15.0 Hz, 1H), 6.56 (m, 1H), 6.49 (m,2H), 5.04 (q, J=18.0 Hz, 2H), 3.08 (s, 3H). MS (DCI/NH₃) m/z 442 (M+H)⁺,m/z 459 (M+NH₄)⁺, m/z 476 (M+2NH₄—H)⁺. Anal. calc. for C₁₉H₁₅F₄N₃O₃S.0.5CH₃COCH₃: C, 52.33; H, 3.85; N, 8.93. Found: C, 52.51; H, 3.58; N, 8.81.

EXAMPLE 3142-(2,2,2-Trifluoroethyl)-4-(2,4-difluoroanilino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 309,substituting 2,4-difluoroaniline in place of 4-aminobenzonitrile toprovide a tan solid (yield: 63.1 mg, 17%). mp 170-175° C. ¹H NMR (300MHz, DMSO) δ 9.00 (s, 1H), 7.80 (s, 1H), 7.57 (d, J=17.4 Hz, 2H), 7.26(d, J=17.4 Hz, 2H), 7.05 (m, 1H), 6.75 (m, 2H), 5.05 (q, J=18.0 Hz, 2H),3.09 (s, 3H). MS (DCI/NH₃) m/z 460 (M+H)⁺, m/z 477 (M+NH₄)⁺. Anal. calc.for C₁₉H₁₄F₅N₃O₃S: C, 49.68; H, 3.07; N, 9.15; found: C, 50.00; H, 2.95;N, 9.10.

EXAMPLE 3152-(2,2,2-Trifluoroethyl)-4-(2,3,5-trifluoroanilino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 309,substituting 2,3,5-trifluoroaniline in place of 4-aminobenzonitrile toprovide a pale purple solid (yield: 85.3 mg, 22%). mp 190-194° C. ¹H NMR(300 MHz, DMSO) δ 9.27 (s, 1H), 7.90 (s, —H), 7.70 (d, J=17.4 Hz, 2H),7.39 (d, J=17.4 Hz, 2H), 7.03 (m, 1H), 6.76 (m, 1H), 5.06 (q, J=18.0 Hz,2H), 3.14 (s, 3H). MS (DCI/NH₃) m/z 495 (M+NH₄)⁺. Anal. calc. forC₁₉H₁₃F₆N₃O₃S: C, 47.80; H, 2.74; N, 8.80. Found: C, 47.51; H, 2.55; N,8.63.

EXAMPLE 3162-(2,2,2-Trifluoroethyl)-4-(4-fluoroanilino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The product was prepared according to the method of Example 309,substituting 4-fluoroaniline in place of 4-aminobenzonitrile to providea tan solid (yield: 15.8 mg, 4%). mp 158-160° C. ¹H NMR (300 MHz, CDCl₃)δ 7.80 (br s, 1H), 7.69 (s, 1H), 7.65 (d, J=18.0 Hz, 2H), 7.18 (d,J=18.0 Hz, 2H), 6.63 (d, J=3.6 Hz, 2H), 6.61 (s, 2H), 4.89 (q, J=17.4Hz, 2H), 2.96 (s, 3H). MS (DCI/NH₃) m/z 459 (M+NH₄)⁺. Anal. calc. forC₁₉H₁₅F₄N₃O₃S.1.25H₂O: C, 49.19; H, 3.80; N, 9.05. Found: C, 59.57; H,3.53; N, 8.70.

EXAMPLE 3172-Benzyl-4-(3-thienyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-Benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneprepared in Example 78 (150 mg, 0.4 mmol), thiophene-3-boronic acid(66.5 mg, 0.52 mmol), CsF (145.8 mg, 0.96 mmol), andtetrakis-(triphenylphosphine)-palladium(0) (13.9 mg, 0.012 mmol) in DME(25 mL) were stirred at reflux for 6 hours TLC (1CH₂Cl₂:1 hexanes:1.5ethyl acetate) indicated that all starting materials were consumed. Thereaction mixture was cooled to room temperature and concentrated underreduced pressure. The residue was partitioned between water and ethylacetate. The organic layer was washed with brine, dried over MgSO₄, andfiltered. The filtrate was concentrated under reduced pressure. Theresidue was purified using a silica gel column (0.5:2.5:0.5CH₂Cl₂/hexanes/ethyl acetate). A yellow powder was obtained (yield: 50mg, 31%). ¹H NMR (300 MHz, CDCl₃) δ 3.09 (s, 3H), 5.41 (s, 2H), 6.72(dd, J=1.5 Hz, 9 Hz, 1H), 7.13 (dd, J=3 Hz, 3 Hz, 1H), 7.3-7.45 (m, 5H),7.5-7.6 (m, 3H), 7.78 (s, 1H), 7.92 (d, 9 Hz, 2H). MS (DCI/NH₃) m/z 423(M+H)⁺. Anal. calc. for C₂₂H₁₈N₂O₃S₂. 0.5H₂O: C, 6.23; H, 4.43; N, 6.49.Found C, 61.29; H, 4.40; N, 6.16.

EXAMPLE 3182-Benzyl-4-(2-benzofuranyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 317,substituting 2-benzofuranboronic acid for 3-thiopheneboronic acid(yield: 46 mg, 25%). ¹H NMR (300 MHz, CDCl₃) δ 3.13 (s, 3H), 5.5 (s,2H), 6.85-6.92 (m, 1H), 7.15-7.25 (m, 3H), 7.3-7.42 (m, 3H), 7.45-7.7(m, 5H), 7.79 (s, 1H) 8.0 (d, J=9 Hz, 2H), 8.08 (s, 1H). MS (DCI/NH₃),m/z 457 (M+H)⁺. Anal. calc. for C₂₆H₂₀N₂O₄S.H₂O: C, 65.80; H, 4.67; N,5.90. Found C, 65.44; H, 4.42; N, 6.14.

EXAMPLE 3192-Benzyl-4-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 221,substituting2-benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone,prepared in Example 78, in place of2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 112 mg, 44%). mp>250° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.20 (s,3H), 5.34 (s, 2H), 5.36 (s, 2H), 7.30-7.44 (m, 6H), 7.48 (d, J=8 Hz,2H), 7.57 (s, 1H), 7.73 (d, J=8 Hz, 1H), 7.85 (d, J=8 Hz, 2H), 8.17 (s,1H). MS (DCI/NH₃) m/z 473 (M+H)⁺, 490 (M+NH₄)⁺. Anal. calc. forC₂₆H₂₀N₂O₅S: C, 65.46; H, 4.33; N, 5.87. Found: C, 65.56; H, 4.48; N,5.75.

EXAMPLE 3202-Benzyl-4-(5-chloro-2-thienyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 317,substituting 5-chloro-2-thiopheneboronic acid in place of3-thiopheneboronic acid (yield: 21 mg, 17%). ¹H NMR (300 MHz, CDCl₃) δ3.15 (s, 3H), 5.45 (s, 2H), 6.51 (d, J=4.5 Hz, 1H), 6.7 (d, J=4.5 Hz,1H), 7.3-7.4 (m, 3H), 7.5=7.6 (m, 4H), 7.6 (s, 1H), 8.05 (d, J=9 Hz,2H). MS (DCI/NH₃), m/z 457 (M+H)⁺. Anal. calc. for C₁₈H₁₅ClN₂O₃S: C,57.68; H, 4.03; N, 7.47. Found C, 57.61; H, 3.84; N, 7.14.

EXAMPLE 3212-Benzyl-4-(3-nitrophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 317,substituting 3-nitrobenzeneboronic acid in place of 3-thiopheneboronicacid (yield: 20 mg, 11%). ¹H NMR (300 MHz, CDCl₃) δ 3.0 (s, 3H), 5.93(s, 2H), 7.6-7.8 (m, 9H), 7.8 (t, J=4.5 Hz, 3H), 8.04 (s, 1H), 8.15 (m,1H). MS (DCI/NH₃), m/z 462 (M+H)⁺. Anal. calc. for C₂₄H₁₉N₃O₅S. 0.75H₂O:C, 60.68; H, 4.35; N, 8.84. Found C, 60.99; H, 3.97; N, 8.35.

EXAMPLE 3222-Benzyl-4-(4-vinylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 317,substituting 4-vinylbenzeneboronic acid in place of 3-thiopheneboronicacid (yield: 40 mg, 23%). ¹H NMR (300 MHz, CDCl₃) δ 3.05 (s, 3H), 5.28(d, J=12 Hz, 1H), 5.41 (s, 2H), 5.74 (d, J=18 Hz, 1H) 6.65 (dd, J=12 Hz,18 Hz, 1H), 7.1-7.6 (m, 11H) 7.83 (d, J=3 Hz, 2H), 7.85 (s, 1H). MS(DCI/NH₃), m/z 443 (M+H)⁺. Anal. calc. for C₂₆H₂₂N₂O₃S: C, 70.57; H,5.01; N, 6.33. Found C, 70.34; H, 4.67; N, 5.97.

EXAMPLE 3232-Benzyl-4-(4-trifluoromethylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 317,substituting 4-(trifluoromethyl)benzeneboronic acid in place of3-thiopheneboronic acid (yield: 101 mg, 52%). ¹H NMR (300 MHz, CDCl₃) δ3.05 (s, 3H), 5.42 (s, 2H), 7.3-7.5 (m, 8H), 7.55-7.6 m, 3H), 7.85 (s,2H), 7.9 (s, 1H). MS (DCI/NH₃) m/z 485 (M+H)⁺. Anal. calc. forC₂₅H₁₉F₃N₂O₃S.0.25H₂O: C, 61.40; H, 4.01; N, 5.72. Found C, 61.26; H,4.01; N, 5.35.

EXAMPLE 3242-Benzyl-4-(2-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 317,substituting 2-methoxybenzeneboronic acid in place of 3-thiopheneboronicacid (yield: 75 mg, 42%). ¹H NMR (300 MHz, CDCl₃) δ 3.01 (s, 3H), 3.5(s, 3H), 5.40 (dd, J=12 Hz, 18 Hz, 2H), 6.76 (d, J=9 Hz, 1H), 6.85-6.95(m, 1H), 7.09 (dd, J=1.5 Hz, 9 Hz, 1H), 7.26-7.41 (m, 6H), 7.55 (dd,J=1.5 Hz, 9 Hz, 2H), 7.82 (d, J=9 Hz, 3H). MS (DCI/NH₃) m/z 447 (M+H)⁺.Anal. calc. for C₂₅H₂₂N₂O₄S.0.5H₂O: C, 65.91; H, 5.08; N, 6.14. Found C,65.86; H, 5.08; N, 5.58.

EXAMPLE 3252-Benzyl-4-(3,4-dimethylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-Benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (150mg, 0.4 mmol) prepared in Example 78 was dissolved in anhydrous DME (10mL) and heated to reflux with 3,4-dimethylbenzeneboronic acid inpresence of CsF (146 mg, 0.96 mmol) andtetrakis(triphenylphosphine)palladium (14 mg, 0.012 mmol) for 0.6 hours.After cooling to room temperature the reaction mixture was diluted withwater and extracted with ethyl acetate (100 mL). The organic layer waswashed with brine, dried over MgSO₄, and evaporated in vacuo. Thecompound was purified on a silica gel column, eluting with 30% ethylacetate in pentanes, providing the desired compound (yield: 100 mg,56%). ¹H NMR (300 MHz, CDCl₃) δ 2.15, 2.20 (2s, 3H), 2.25, 2.30 (2s,3H), 3.05, 3.08 (2s, 3H), 5.35, 5.40 (2s, 2H), 6.60-7.1 (m, 3H),7.3077.40 (m, 4H), 7.42-7.60 (m, 2H), 7.70-8.02 (m, 4H). MS (DCI/NH₃)m/z 445 (M+H)⁺. Anal. calc. for C₂₆H₂₄N₂O₃S.H₂O: C, 67.51; H, 5.66; N,6.05. Found: C, 67.45; H, 5.56; N, 5.85.

EXAMPLE 3262-Benzyl-4-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 325,substituting 3-fluoro-4-methoxybenzeneboronic acid in place of3,4-dimethylbenzeneboronic acid (yield: 35 mg, 19%). ¹H NMR (300 MHz,CDCl₃) δ 3.05 (s, 3H), 3.85 (s, 3H), 5.3, 5.4 (2s, 2H), 6.75-7.03 (m,3H), 7.3-7.40 (m, 5H), 7.4-7.55 (dd, J=1.5 Hz; 7.5 Hz, 2H), 7.8-7.95 (m,3H). MS (DCI/NH₃) m/z 465 (M+H)⁺. Anal. calc. for C₂₅H₂₁N₂O₄S.0.25H₂O:C, 64.02; H, 4.62; N, 5.97. Found: C, 63.93; H, 4.54; N, 5.43

EXAMPLE 3272-Benzyl-4(2-methoxy-pyrid-3-yl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 325,substituting 2-methoxy-3-pyridylboronic acid in place of3,4-dimethylbenzeneboronic acid (yield: 35 mg, 19%). ¹H NMR (300 MHz,CDCl₃) δ 3.05 (s, 3H), 3.58 (s, 3H), 5.4 (dd, J=15 Hz, 18 Hz; 2H), 6.88(m, 1H), 7.28-7.40 (m, 5H), 7.5-7.6 (dd, J=1.5 Hz; 7.5 Hz, 3H), 7.82 (s,1H), 7.85 (d, J=18 Hz, 2H), 8.15 (br s, 1H). MS (DCI/NH₃) m/z 448(M+H)⁺. Anal. calc. for C₂₄H₂₁N₃O₄S: C, 64.42; H, 4.73; N, 9.39. Found:C, 64.17; H, 5.11; N, 9.04

EXAMPLE 3282-Benzyl-4-(3-ethoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 325,substituting 3-ethoxybenzeneboronic acid in place of3,4-dimethylbenzeneboronic acid (yield: 115 mg, 67%). ¹H NMR (300 MHz,CDCl₃) δ 1.31 (t, J=7.5 Hz, 3H), 3.05 (s, 3H), 3.89 (q, J=7.5 Hz, 2H),5.14 (s, 2H), 6.65 (d, J=9 Hz, 1H), 6.72 (t, J=1.5 Hz, 1H), 6.8 (dd,J=1.5 Hz, 9 Hz, 1H), 7.15 (t, J=9 Hz, 1H), 7.3-7.4 (m, 5H), 7.5-7.6 (m,2H), 7.85 (d, J=9 Hz, 3H). MS (DCI/NH₃) m/z 461 (M+H)⁺. Anal. calc. forC₂₆H₂₄N₂O₄S.0.5H₂O: C, 66.50; H, 5.36; N, 5.96. Found: C, 66.39; H,5.02; N, 5.77

EXAMPLE 3292-Benzyl-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-(2H)-pyridazinoneEXAMPLE 329A 2-Benzyl-4,5-dibromo-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 194A,substituting benzyl hydrazine hydrochloride in place of 4-fluorophenylhydrazine hydrochloride (yield: 7.86 g, 60%). ¹H NMR (300 MHz, DMSO d₆)δ 5.27 (s, 2H), 7.26-7.41 (m, 5H), 8.19 (s, 1H). MS DCI/NH₃) m/z 345(M+H)⁺, 362 (M+H)⁺.

EXAMPLE 329B 2-Benzyl-5-bromo-4-methoxy-3(2H)-pyridazinone

The title compound was prepared according to the method described inExample 194B, substituting 2-benzyl-4,5-dibromo-3(2H)-pyridazinone for2-(4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone (yield: 2.877 g; 85%).¹H NMR (300 MHz, DMSO-d₆) δ 4.14 (s, 3H), 5.23 (s, 2H), 7.26-7.38 (m,5H), 8.11 (s, 1H). MS (DCl/NH₃) m/z 295 (M+H)⁺, 312 (M+NH₄)⁺.

EXAMPLE 329C2-Benzyl-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method described inExample 6, substituting 2-benzyl-4-methoxy-5-bromo-3(2H)-pyridazinonefor 2-benzyl-4-methoxy-5-bromo-3(2H)-pyridazinone (yield: 3.705 g). ¹HNMR (300 MHz, DMSO-d₆) δ 2.52 (s, 3H), 3.99 (s, 3H), 5.28 (s, 2H),7.26-7.41 (m, 7H), 7.55 (m, 2H), 8.02 (s, 1H). MS (DCl—NH₃) m/z 339(M+H)⁺, 356 (M+NH₄)⁺.

EXAMPLE 329D2-Benzyl-4-(4-fluorobenzyl-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,substituting 4-fluorobenzyl magnesium chloride in place ofcyclohexylmagnesium chloride and2-benzyl-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone wassubstituted in place of2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone.

EXAMPLE 329E2-Benzyl-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-(2H)-pyridazinone

The sulfide compound, Example 329D, was oxidized to the methyl sulfonylcompound according to the method of Example 10. mp 186-189° C. ¹H NMR(300 MHz, DMSO d₆) δ 3.27 (s, 3H), 3.83 (s, 2H), 5.31 (s, 2H), 6.94-7.05(m, 4H), 7.27-7.40 (m, 5H), 7.67 (m, 2H), 7.94 (s, 1H), 8.03 (m, 2H). MS(DCI/NH₃) M/Z 449 (M+H)⁺, 466 (M+NH₄)⁺. Anal. calc. for C₂₅H₂₁FN₂O₃S: C,66.95; H, 4.72; N, 6.25. Found: C, 66.68; H, 4.75; N, 6.14.

EXAMPLE 3302-(tert-Butyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 330A 2-(tert-Butyl)-4,5-dichloro-3(2H)-pyridazinone

A solution of mucochloric acid (33.8 g, 200 mmol) andtert.-butylhydrazine hydrochloride (24.9 g, 200 mmol) in methanol (400mL) was stirred at reflux overnight. Methanol was removed in vacuo andthe residue was partitioned between ether and water. The organic layerwas dried over MgSO₄ and filtered. The filtrate was concentrated invacuo and the residue was purified by column chromatography (silica gel,100% hexanes). Product-containing fractions were combined and the titlecompound was crystallized from ether/hexanes (yield: 10.0 g, 22.6%). mp63-64° C. ¹H NMR (300 MHz, CDCl₃) δ 1.65 (s, 9H), 7.73 (s, 1H). MS(DCI/NH₃) m/z 221 (M+H)⁺, 238 (M+NH₄)⁺.

EXAMPLE 330B2-(tert-Butyl)-4-(3-methylbutoxy)-5-chloro-3(2H)-pyridazinone

A stirred, room temperature solution of 3-methyl-1-butanol (0.5 mL, 4.52mmol) in tetrahydrofuran (10 mL) was treated with a 60% oil suspensionof sodium hydride (0.24 g, 5.88 mmol). After 5 minutes, hydrogen gasevolution had subsided, so the dichloro-intermediate from Example 330A(1.0 g, 4.52 mmol) was added and the reaction mixture was stirred atroom temperature for 20 hours. The reaction was quenched with 10%aqueous citric acid and extracted with ethyl acetate. The organic layerwas washed with brine, dried over MgSO₄, and filtered. The filtrate wasconcentrated in vacuo, and the residue was purified by columnchromatography (silica gel, 100% hexanes). The title compound wasobtained as a pale yellow oil (yield: 0.7 g, 56.7%). ¹H NMR (300 MHz,CDCl₃) δ 0.95 (d, J=6 Hz, 6H), 1.63 (s, 9H), 1.64 (q, J=6 Hz, 2H), 1.85(nonet, J=6 Hz, 1H), 4.49 (t, J=6 Hz, 2H), 7.64 (s, 1H). MS (DCI/NH₃)m/z 273 (M+H)⁺, 290 (M+NH₄)⁺.

EXAMPLE 330C.2-(tert-Butyl)-4-(3-methylbutoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

A solution of the intermediate from Example 330B (700 mg, 2.57 mmol),4-(methylthio)benzeneboronic acid (560 mg, 3.34 mmol), cesium carbonate(2.17 g, 6.67 mmol), and tetrakis(triphenylphosphine)palladium(0) (210mg, 0.18 mmol) in dimethoxyethane (40 mL) was heated at reflux for 5hours. The heat source was then removed and the reaction mixture wasstirred at room temperature for 64 hours. The reaction mixture wasfiltered and the filtrate was concentrated in vacuo to provide a brownoil. This oil was purified by column chromatography twice (silica gel,97:3 hexanes/ethyl acetate, then 96:4 hexanes/ethyl acetate) to providea semi-solid product (yield: 270 mg, 29.2%). ¹H NMR (300 MHz, CDCl₃) δ0.81 (d, J=6 Hz, 6H), 1.49 (q, J=6 Hz, 2H), 1.63 (nonet, J=6 Hz, 1H),1.69 (s, 9H), 2.52 (s, 3H), 7.32 (d, J=9 Hz, 2H), 7.50 (d, J=9 Hz, 2H),7.73 (s, 1H). MS (DCI) m/z 361 (M+H)⁺.

EXAMPLE 330D2-(tert-Butyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 10,substituting2-(tert.-butyl)-4-(3-methylbutoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonefor 4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(yield: 188 mg, 63.9%). mp 138-139° C. ¹H NMR (300 MHz, CDCl₃) δ 0.81(d, J=6 Hz, 2H), 1.48 (q, J=6 Hz, 2H), 1.48-1.68 (m, 1H), 1.69 (s, 9H),3.10 (s, 3H), 4.38 (t, J=6 Hz, 2H), 7.71 (s, 1H), 7.74 (d, J=9 Hz, 2H),8.03 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 393 (M+H)⁺. Anal. calc. forC₂₀H₂₈N₂O₄S: C, 61.20; H, 7.19; N, 7.14. Found: C, 61.13; H, 7.23; N,6.89.

EXAMPLE 3312-(3-Chlorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 10,substituting2-(3-chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(Example 207C) in place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(yield: 3.31 g, 96%). mp 112-114° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.31(m, 3H), 4.10 (m, 3H), 7.52-7.65 (m, 3H), 7.75 (m, 1H), 7.90 (m, 2H),8.07 (m, 2H), 8.21 (s, 1H). MS (DCI/NH₃) m/z 391 (M+H)⁺, 408 (M+NH₄)⁺.Anal. calc. for: C₁₈H₁₅ClN₂O₄S.0.25H₂O: C, 54.68; H, 3.95; N, 7.08.Found: C, 54.59; H, 3.65; N, 6.98.

EXAMPLE 3322-(3-Chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A suspension of2-(3-chlorophenyl)-4-(methoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(6.26 g, 16 mmol) in 5% NaOH (54 mL) dioxane (39.4 mL) was heated atreflux and stirred for 1.5 hours. As the reaction proceeds, the solutionbecomes orange and homogeneous. The mixture was cooled and poured into1N HCl, with constant stirring. The resulting white solid was filteredand rinsed with H₂O and left to dry overnight. The mostly dry productwas taken up in CH₂Cl₂ and azeotroped with toluene to remove anyremaining H₂O, to provide the desired product as a white solid (yield:6.79 g, >100%). ¹H NMR (300 MHz, DMSO d₆) δ 2.27 (s, 3H), 7.51-7.62 (m,2H), 7.68 (m, 1H), 7.79 (m, 1H), 8.03 (m, 4H), 8.24 (s, 1H). MS(DCI/NH₃) m/z 377 (M+H)⁺, 396 (M+NH₄)⁺.

EXAMPLE 3332-(3-Chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

To a 0° C. solution of2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone,prepared in Example 332, (6.79 g, 16 mmol) in pyridine (160 mL) wasadded p-toluenesulfonyl chloride (3.06 g, 16 mmol). The solution wasleft to warm slowly to room temperature with stirring under nitrogen.After 2.5 hours, the mixture was poured into H₂O with constant stirring.The resulting off-white solid was filtered, rinsed with H₂O and dried toprovide the desired product (yield: 6.26 g, 79%). mp 198-200° C. ¹H NMR(300 MHz, DMSO d₆) δ 2.35 (s, 3H), 3.28 (s, 3H), 7.20 (m, 2H), 7.52-7.64(M, 5H), 7.70 (m, 3H), 7.89 (m, 2H), 8.32 (s, 1H). MS APCI+531 (M+H)⁺,548 (M+H₂O)⁺, APCI-493 (M+35)⁻. Anal. calc. for C₂₄H₁₉ClN₂O₆S₂: C,54.29; H, 3.61; N, 5.28. Found: C, 54.55; H, 3.46; —N, 5.57.

EXAMPLE 3342-(3-Chlorophenyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A solution of2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone,prepared in Example 332, in POCl₃ was heated to reflux for 3 hours whilestirring under nitrogen. The mixture was cooled to room temperature andpoured into ice with constant swirling. The resulting white solid wasextracted with ethyl acetate. The combined organics were washed withH₂O, dried over MgSO₄, and concentrated to a solid. The crude productwas purified using flash chromatography (SiO₂, eluting with 1:1 ethylacetate/hexanes) to provide the desired product (yield: 0.151 g, 29%).mp 203-204° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.29-3.36 (3H, obstructed byH₂O), 7.60 (m, 3H), 7.76 (m, 1H), 7.92 (m, 2H), 8.14 (m, 2H), 8.25 (s,1H). MS (DCI/NH₃) m/z 395 (M+H)⁺, 412 (M+NH₄)⁺. Anal. calc. forC₁₇H₁₂Cl₂N₂O₃S: C, 51.66; H, 3.06; N, 7.09. Found: C, 51.67; H, 3.03; N,6.93.

EXAMPLE 3352-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

To a stirred suspension of2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone,prepared in Example 333, (0.175 g, 0.33 mmol) in THF (3.3 mL) was addedisobutanol (0.03 mL, 0.33 mmol), and NaH (0.0132 g, 0.33 mmol). Theresulting solution was stirred under nitrogen for 1 hour. The reactionwas poured into H₂O and extracted with ethyl acetate. The combinedorganics were dried over MgSO₄ and concentrated in vacuo. The crudesolid was purified using flash chromatography (SiO₂, 2:1 hexanes:ethylacetate) to provide the desired product (yield: 0.1088 g 76%). mp166-169° C. ¹H NMR (300 MHz, DMSO d₆) δ 0.78 (d, J=6 Hz, 6H), 1.84 (m,1H), 3.29 (s, 3H), 4.20 (d, J=6 Hz, 2H), 7.51-7.63 (m, 3H), 7.76 (m,1H), 7.92 (m, 2H), 8.07 (m, 2H), 8.21 (s, 1H). MS (DCI/NH₃) m/z 433(M+H)⁺, 450 (M+NH₄)⁺. Anal. calc. for C₂₁H₂₁ClN₂O₄S: C, 57.07; H, 5.01;N, 6.33. Found: C, 57.06; H, 4.78; N, 6.13.

EXAMPLE 3362-(3-Chlorophenyl)-4-(t-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting t-butanol in place of isobutanol (yield: 0.093 g, 66%). mp232-235° C. ¹H NMR (300 MHz, DMSO d₆) δ 1.18 (s, 9H), 3.30 (s, 3H),7.52-7.64 (m, 3H), 7.74 (m, 1H), 7.92 (m, 2H), 8.08 (m, 2H), 8.20 (s,1H). MS (DCI/NH₃) m/z 433 (M+H)⁺, 450 (M+NH₄)⁺. Anal. calc. forC₂₁H₂₁ClN₂O₄S: C, 58.26; H, 4.89; N, 6.47. Found: C, 58.21; H, 4.88; N,6.28.

EXAMPLE 3372-(3-Chlorophenyl)-4-(cyclohexyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting cyclohexanol in place of isobutanol (yield: 0.139 g, 92%)semi-solid; ¹H NMR-(300 MHz, CDCl₃) δ 1.09-1.50 (m, 6H), 1.57 (m, 2H),1.88 (m, 2H), 3.13 (s, 3H), 5.19 (m, 1H), 7.38-7.48 (m, 2H), 7.59 (m,1H), 7.70 (m, 1H), 7.83 (m, 2H), 7.92 (s, 1H), 8.07 (m, 2H). MS APCI+459(M+H) 476 (M+H₂O)⁺, APCI-458 (M)-, 493 (M+35)⁻. Anal. calc. forC₂₃H₂₃ClN₂O₄S.0.25H₂O: C, 59.60; H, 5.11; N, 6.04. Found: C, 59.48; H,4.86; N, 5.88.

EXAMPLE 3382-(3-Chlorophenyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting neopentyl alcohol in place of isobutanol (yield: 0.109 g,74%). mp 151-153° C. ¹H NMR (300 MHz, DMSO d₆) δ 0.78 (s, 9H), 3.29 (s,3H), 4.10 (s, 2H), 7.52-7.64 (m, 3H), 7.76 (m, 1H), 7.92 (m, 2H), 8.07(m, 2H), 8.20 (s, 1H). MS (DCI/NH₃) m/z 447 (M+H)⁺, 464 (M+NH₄)⁺. Anal.calc. for C₂₂H₂₃ClN₂O₄S: C, 59.12; H, 5.19; N, 6.27. Found C, 59.40; H,5.31; N, 5.99.

EXAMPLE 3392-(3-Chlorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)Phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting 3-methyl-1-butanol in place of isobutanol (yield: 0.229 g,80.5%). mp 134-135° C. ¹H NMR (300 MHz, DMSO d₆) δ 0.79 (d, J=6 Hz, 6H),1.42-1.64 (m, 3H), 3.30 (s, 3H), 4.43 (t, J=6 Hz, 2H), 7.52-7.65 (m,3H), 7.76 (m, 1H), 7.90 (m, 2H), 8.07 (m, 2H), 8.21 (s, 1H). MS (DC/NH₃)m/z 447 (M+H)⁺, 464 (M+NH₄)⁺. Anal. calc. for C₂₂H₂₃ClN₂O₄S: c, 59.12;H, 5.19; N, 6.27. Found: C, 58.91; H, 5.12; N, 6.01.

EXAMPLE 3402-(3-Chlorophenyl)-4-(3-octyn-1-yloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting 3-octyn-1-ol in place of isobutanol (yield: 0.128 g, 77%).Oil. ¹H NMR (300 MHz, CDCl₃) δ 0.88 (m, 3H), 1.25-1.44 (m, 4H), 2.05 (m,2H), 2.52 (m, 2H), 4.68 (t, J=6 Hz, 2H), 7.43 (m, 2H), 7.59 (m, 1H),7.70 (m, 1H), 7.86 (m, 2H), 7.92 (s, 1H). MS (DCI/NH₃) m/z 485 (M+H)⁺.Anal. calc. for C₂₅H₂₅ClN₂O₄S: C, 61.94; H, 5.20; N, 5.78. Found: C,61.82; H, 4.99; N, 5.57.

EXAMPLE 3412-(3-Chlorophenyl)-4-[2-(di-ethylamino)ethoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting N,N-(dimethyl)ethanolamine in place of isobutanol (yield:0.111 g, 75%). mp 110-113° C. ¹H NMR (300 MHz, DMSO d₆) δ 2.29 (bs, 6H),2.68 (bs, 2H), 4.68 (t, J=5 Hz, 2H), 7.38-7.48 (m, 2H), 7.57 (m, 1H),7.68 (m, 1H), 7.89 (m, 2H), 8.07 (m, 2H). MS (DCI/NH₃) m/z 448 (M+H)⁺.Anal. calc. for C₂₁H₂₂ClN₃O₄S.0.50H₂O: C, 55.19; H, 5.07; N, 9.19.Found: C, 55.24; H, 4.97; N, 9.07.

EXAMPLE 3422-(3-Chlorophenyl)-4-[2-methyl-1-(1-methylethyl)propoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting 2,4-dimethyl-3-pentanol in place of isobutanol (yield:0.075 g, 48%). Semi-solid; ¹H NMR (300 MHz, DMSO d₆) δ 0.79 (m, 12H),1.78-1.92 (m, J=6 Hz, 2H), 3.29 (s, 3H), 5.40 (t, J=6 Hz, 1H), 7.57 (m,3H), 7.72 (m, 1H), 7.91 (m, 2H), δ 07 (m, 2H), 8.17 (m, 1H). MS(DCI/NH₃) m/z 475 (M+H)⁺, 492 (M+NH₄)⁺. Anal. calc. for C₂₄H₂₇ClN₂O₄S(0.75H₂O): C, 59.00; H, 5.88; N, 5.78. Found: C, 58.83; H, 5.74; N,5.52.

EXAMPLE 3432-(3-Chlorophenyl)-4-(Phenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting phenol in place of isobutanol (yield: 0.053 g, 35%). mp205-207° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.28 (s, 3H), 7.08 (m, 3H), 7.31(m, 2H), 7.50-7.64 (m, 3H), 7.73 (m, 1H), 7.90 (m, 2H), 8.05 (m, 2H),8.40 (s, 1H). MS (DCI/NH₃) m/z 453 (M+H)⁺, 470 (M+NH₄)⁺. Anal. calc. forC₂₃H₁₇ClN₂O₄S: C, 60.99; H, 3.78; N, 6.19. Found: C, 60.79; H, 3.65; N,5.87.

EXAMPLE 3442-(3-Chlorophenyl)-4-[3-(dimethylamino)phenoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting 3-(dimethylamino)phenol in place of isobutanol (yield:0.057 g, 60%). mp 191-193; ¹H NMR (300 MHz, DMSO d₆) δ 2.85 (s, 6H),3.27 (s, 3H), 6.36 (m, 3H), 7.05 (m, 1H), 7.51-7.63 (m, 3H), 7.72 (m,1H), 7.90 (m, 2H), 8.05 (m, 2H), 8.39 (s, 1H). MS APCI+495 (M+H)⁺,APCI−, 495 (M)-, 590 (M+35)⁻. Anal. calc. for C₂₅H₂₂ClN₃O₄S: C, 60.54;H, 4.47; N, 8.47. Found: C, 60.04; H, 4.49; N, 8.26.

EXAMPLE 3452-(3-Chlorophenyl)-4-(4-methoxyphenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting 4-methoxyphenol in place of isobutanol (yield: 0.080 g,69%). mp 182-184° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.27 (s, 3H), 3.70 (s,3H), 6.84 (m, 2H), 7.00 (m, 2H), 7.56 (m, 3H), 7.72 (m, 1H), 7.90 (m,2H), 8.04 (m, 2H), 8.38 (s, 1H). MS (DCI/NH₃) m/z 483 (M+H)⁺, 500(M+NH₄)⁺. Anal. calc. for C₂₄H₁₀₉ClN₂O₅S: C, 59.64; H, 3.97; N, 5.80.Found: C, 59.86; H, 3.94; N, 5.62.

EXAMPLE 3462-(3,4-Difluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 150 mg, 61%). mp 116-117° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.78(d, 6H), 1.84, (m, 1H), 3.3 (s, 3H), 4.2 (d, 2H), 7.54 (m, 1H), 7.6 (m,1H), 7.82 (m, 1H), 7.91 (d, 2H), 8.07 (d, 2H), 8.21 (s, 1H). MS(DCI/NH₃) m/z 435 (M+H)⁺, 452 (M+NH₄)+Anal. calc. for C₂₁F₂H₂₀N₂O₄S: C,58.06; H, 4.64; N, 6.45.

EXAMPLE 3472-(3,4-Difluorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 346substituting 3-methyl-1-butanol in place of isobutanol (yield: 63 mg,23%). mp 121-123° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.78 (d, 6H), 1.48, (m,3H), 3.3 (s, 3H), 4.43 (t, 2H), 7.54 (m, 1H), 7.6 (m, 1H), 7.82 (m, 1H),7.91 (d, J=9 Hz, 2H), 8.07 (d, J=9 Hz, 2H), 8.2 (s, 1H). MS (DCI/NH₃)m/z 449 (M+H)⁺, 466 (M+NH₄)⁺. Anal. calc. for C₂₂H₂₂F₂N₂O₄S: C, 58.92;H, 4.94; N, 6.25. Found, C, 59.22; H, 4.97; N, 6.07.

EXAMPLE 3482-(3,4-Difluorophenyl)-4-(4-fluorophenoxy)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 346,starting with2-(3,4-difluorophenyl)-4-tosyloxy-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand substituting 4-fluorophenol in place of isobutanol mp 168-170° C. ¹HNMR (300 MHz, DMSO-d₆) δ 3.39 (s, 3H), 7.15 (d, 4H), 7.51 (m, 1H), 7.6(m, 1H) 7.75 (m, 3H), 7.97 (t, 1H); 8.4 (s, 1H). MS (DCI/NH₃) m/z 491(M+H)⁺, 508 (M+NH₄)⁺. Anal. calc. for C₂₃H₁₄F₄N₂O₄S: C, 56.33; H, 2.88;N, 5.71. Found, C, 56.07; H, 2.94; N, 5.33.

EXAMPLE 3492-(3,4-Difluorophenyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 346substituting neopentyl alcohol in place of isobutanol (yield: 1.18 g,94%). mp 126-128° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.78 (s, 9H), 3.3 (s,3H), 4.1 (s, 2H), 7.51 (m, 1H), 7.6 (m, 1H), 7.82 (m, 1H), 7.91 (d, J=9Hz, 2H), 8.07 (d, J=9 Hz, 2H), 8.21 (s, 1H). MS (DCI/NH₃) m/z 449(M+H)⁺, 466 (M+NH₄)⁺. Anal. calc. for C₂₂H₂₂F₂N₂O₄S: C, 58.92; H, 4.94;N, 6.25. Found: C, 59.03; H, 5.03; N, 6.18.

EXAMPLE 3502-(3,4-Difluorophenyl)-4-[2-(isopropoxy)ethoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 346substituting 2-(isopropoxy)ethanol in place of isobutanol (yield: 432mg, 72%). mp 105-107° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (d, 6H), 3.3(s, 3H), 3.43 (m, 1H), 3.54 (m, 2H), 4.63 (m, 2H), 7.54 (m, 1H), 7.6 (m,1H), 7.8 (m, 1H), 8.01 (m, 4H), 8.2 (s, 1H). MS (DCI/NH₃) m/z 465(M+H)⁺, 482 (M+NH₄)⁺. Anal. calc. for C₂₂H₂₂F₂N₂O₅S: C, 56.89; H, 4.77;N, 6.03. Found, C, 57.03; H, 4.65; N, 5.83.

EXAMPLE 3512-(3,4-Difluorophenyl)-4-(3-methylpentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 346substituting 3-methylpentyl-1-ol in place of isobutanol (yield: 400 mg,80%). mp 100-102° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.75 (m, 6H), 1.05 (m,1H), 1.28 (m, 3H) 1.6 (m, 1H), 3.3 (s, 3H), 4.45 (m, 2H), 7.5 (m, 1H),7.6 (m, 1H), 7.8 (m, 1H), 7.9 (d, J=9 Hz, 2H) 8.05 (d, J=9 Hz, 2H), 8.2(s, 1H). MS (DCI/NH₃) m/z 463 (M+H)⁺, 480 (M+NH₄)⁺. Anal. calc. forC₂₃H₂₄F₂N₂O₄S: C, 59.73; H, 5.23; N, 6.06. Found, C, 59.78; H, 5.31; N,6.00.

EXAMPLE 3522-(3,4-Difluorophenyl)-4-(4-methyl-3-penten-1-yloxy)-5-[4-(methylsulfonyl)phenyl]-5-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 346substituting 4-methyl-3-pentene-1-ol in place of isobutanol (yield: 405mg, 67.8%). mp 88-90° C. ¹H NMR (300 MHz, DMSO-d₆) δ 1.5 (di 6H), 2.27(m, 2H) 3.3 (s, 3H), 4.43 (t, 2H), 4.95 (m, 1H), 7.5 (m, 1H), 7.6 (m,1H), 7.8 (m, 1H), 7.9 (d, 2H), 8.06 (d, 2H), 8.2 (s, 1H). MS (DCI/NH₃)m/z 461 (M+H), 478 (M+NH₄)⁺. Anal. calc. for C₂₃H₂₂F₂N₂O₄S: C, 59.99; H,4.82; N, 6.08. Found, C, 59.88; H, 4.76; N, 5.84.

EXAMPLE 3532-(3,4-Difluorophenyl)-4-[3-(methoxy)butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 346substituting 3-methoxybutyl-1-ol in place of isobutanol (yield: 350 mg,68%). mp 99-101° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.97 (d, 3H), 1.7 (m,2H), 3.05 (s, 3H), 3.2 (m, 1H) 3.3 (s, 3H), 4.45 (m, 2H), 7.54 (m, 1H),7.6 (m, 1H), 7.8 (m, 1H), 7.9 (d, J=9 Hz, 2H) 8.01 (d, J=9 Hz, 2H), 8.2(s, 1H). MS (DCI/NH₃) m/z 465 (M+H)⁺, 482 M+NH₄)⁺. Anal. calc. forC₂₂H₂₂F₂N₂O₅S: C, 56.89; H, 4.77; N, 6.03. Found, C, 56.60; H, 4.83; N,5.96.

EXAMPLE 3542-(3-Chlorophenyl)-4-(N-methylbenzylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

To a rapidly stirred 0° C. mixture of N-methylbenzylamine (67.5 mg, 0.56mmol) and tetrahydrofuran (3.7 mL) was slowly added dropwise an n-BuLisolution (0.235 mL, 0.59 mmol, 2.5 M in hexanes). The reaction mixturewas stirred for 10 minutes at 0° C. and 1 hour at 23° C. The solutionwas cooled to −78° C., and a tetrahydrofuran (10-15 mL) solution of the2-(3-chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(200 mg, 0.56 mmol) slowly added along the interior wall of the reactionvessel. This reaction mixture was stirred overnight, slowly warming to23° C. as the cooling bath evaporated. The reaction was quenched withwater and diluted with a large excess of ethyl acetate. The layers wereseparated, and the ethyl acetate layer washed with additional water andbrine and dried over MgSO₄, filtered, and concentrated in vacuo. Theresidue was chromatographed (flash silica gel, ethyl acetate/hexanes1:9) to provide 2-(3-chlorophenyl)-4-(N-methylbenzylamino)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 145 mg,58%).

The title compound was prepared according to the method of Example 10,substituting2-(3-chlorophenyl)-4-(N-methylbenzylamino)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonein place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(yield: 143 mg, 95%). mp 60-85° C. ¹H NMR (300 MHz, CDCl₃) δ 2.46 (s,3H), 3.09 (s, 3H), 4.63 (s, 2H), 7.19 (d, J=8.7 Hz, 2H), 7.24-7.29 (m,2H), 7.32-7.48 (m, 5H), 7.60 (ddd, J=7.2, 1.8, 1.8 Hz, 1H), 7.67 (s,1H), 7.70 (dd, J=1.8, 1.8 Hz, 1H), 7.91 (d, J=8.7 Hz, 2H). MS (APCI+)m/z 480 (M+H)⁺.

EXAMPLE 3552-(4-Fluorophenyl)-4-(1-piperidinyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

To a slightly heterogeneous solution of piperidine (99.7 mg, 1.17 mmol)and toluene (8 mL) cooled to −78° C. was slowly added dropwise an n-BuLisolution (0.235 mL, 0.59 mmol, 2.5 M in hexanes). After stirring at −78°C. for 10 minutes, the cooling bath was removed and the mixture stirredan additional 1 hour at 23° C. The2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(400 mg, 1.17 mmol) was dissolved in portions in toluene (3×6-7 mLaliquots) with a heat gun and cooled to 0° C. prior to transfer viasyringe to the lithium amide solution (cooled to −78° C.). The additionwas made slowly along the interior wall of the reaction vessel. Thisreaction mixture was stirred overnight, slowly warning to 23° C. as thecooling bath evaporated. The reaction was quenched with water anddiluted with a large excess of ethyl acetate. The layers were separated,and the ethyl acetate layer washed with additional water and brine anddried over MgSO₄, filtered, and concentrated in vacuo. The residue waschromatographed (flash silica gel, ethyl acetate/hexanes 1:2) to provide440 mg 95%) of2-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-4-piperidino-3(2H)-pyridazinone.

The title compound was prepared according to the method of Example 10,substituting2-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-4-piperidino-3(2H)-pyridazinonein place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(yield: 165 mg, 98%). mp 80-100° C. ¹H NMR (300 MHz, CDCl₃) δ 1.59 (brs, 6H), 2.59 (br s, 4H), 3.14 (s, 3H), 7.17 (dd, J=8.7, 8.7 Hz, 2H),7.51 (d, J=8.7 Hz, 2H), 7.55-7.62 (m, 2H), 7.68 (s, 1H), 8.06 (d, J=8.7Hz, 2H). MS (APCI+) m/z 428 (M+H)⁺. Powdered out in CH₂Cl₂/C₆H₁₄. Anal.calc. for C₂₂H₂₂FN₃O₃S.0.25C₆H₁₄: C, 62.85; H, 5.72; N, 9.35. Found: C,62.46; H, 5.77; N, 9.13.

EXAMPLE 3562-(4-Fluorophenyl)-4-(1-pyrrolidinyl)-1-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 355,substituting pyrrolidine for piperidine (yield: 107 mg, 82%). mp192-195° C. ¹H NMR (300 MHz, CDCl₃) δ 1.71-1.80 (m, 4H), 3.13 (s, 3H),3.40-3.49 (m, 4H), 7.16 (dd, J=8.7, 8.7 Hz, 2H), 7.47-7.60 (m, 5H), 7.99(d, J=8.7 Hz, 2H). MS (APCI+) m/z 414 (M+H)⁺. Anal. calc. forC₂₁H₂₀FN₃O₃S: C, 61.00; H, 4.87; N, 10.16. Found: C, 60.95; H, 4.94; N,10.07.

EXAMPLE 3572-(3-Chlorophenyl)-4-(4-methylphenylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

To a stirred suspension of2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone,prepared in Example 333, (0.0802 g, 0.15 mmol) in EtOH (1.5 mL) wasadded thiocresol (0.019 g, 0.15 mmol) and K₂CO₃ (0.0203 g, 0.15 mmol).The suspension was heated to 50° C. with stirring for 2.5 hours. Themixture was poured into H₂O with constant stirring. The resultingprecipitate was filtered, rinsed with H₂O and dried to provide thedesired product (yield: 0.060 g, 83%). mp 178-178° C. ¹H NMR (300 MHz,DMSO d₆) δ 2.19 (s, 3H), 3.23 (s, 3H), 6.95 (m, 2H), 7.08 (m, 2H),7.52-7.66 (m, 3H), 7.72 (m, 1H), 7.88 (m, 2H), 8.08 (s, 1H). MS(DCI/NH₃) m/z 483 (M+H)⁺, 500 (M+NH₄)⁺. Anal. calc. for:C₂₄H₁₉ClN₂O₃S₂.0.75H₂O: C, 58.05; H, 4.16; N, 5.64. Found: C, 57.99; H,3.69; N, 5.76.

EXAMPLE 3582-(3-Chlorophenyl)-4-(2-pyridylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 357,substituting 2-mercaptopyridine in place of thiocresol (yield: 0.061 g,39%). mp 110-114° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.28 (s, 3H), 7.16 (m,1H), 7.37 (m, 1H), 7.51-7.71 (m, 5H), 7.81 (m, 2H), 8.03 (m, 2H), 8.27(s, 1H), 8.34 (m, 1H). MS (DCI/NH₃) m/z 470 (M+H)⁺. Anal. calc. forC₂₂H₁₆ClN₃O₃S₂.0.50H₂O: C, 55.16; H, 3.57; N, 8.77. Found: C, 54.88; H,3.19; N, 8.59.

EXAMPLE 3592-(3-Chlorophenyl)-4-(phenylmethylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

To a stirred suspension of2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone,prepared in Example 333, (0.175 g, 0.33 mmol) in THF (3.3 mL) was addedbenzyl mercaptan (0.04 mL, 0.33 mmol) and TEA (0.046 mL, 0.33 mmol). Theresulting solution was stirred at room temperature under nitrogen for 1hour. The mixture was poured into H₂O and extracted with ethyl acetate.The combined organics were dried over MgSO₄ and concentrated in vacuo.The resulting crude product was purified using flash chromatography(SiO₂, 2:1 hexanes:ethyl acetate) to provide the desired product (yield:0.136 g 85%). mp 142-145° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.31 (s, 3H),4.36 (s, 2H), 7.17 (m, 2H), 7.21-7.33 (m, 3H), 7.51 (m, 2H), 7.57-7.64(m, 3H), 7.74 (m, 1H), 8.01 (m, 2H). MS (DCI/NH₃) m/z 483 (M+H)⁺, 500(M+NH₄)⁺. Anal. calc. for C₂₄H₁₉ClN₂O₃S₂: C, 59.68; H, 3.96; N, 5.80.Found: C, 59.40; H, 4.11; N, 5.71.

EXAMPLE 3602-(3-Chlorophenyl)-4-(2-furylmethylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 359,substituting furfuryl mercaptan in place of benzyl mercaptan (yield:0.162 g, 100%). mp 140-149° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.31 (s, 3H),4.46 (s, 2H), 6.20 (m, 1H), 6.37 (m, 1H), 7.50-7.67 (m, 6H), 7.77 (m,1H), 8.03 (m, 2H), 8.08 (s, 1H). MS (DCI/NH₃) m/z 473 (M+H)⁺, 490(M+NH₄)⁺. Anal. calc. for C₂₂H₁₇ClN₂O₄S₂: C, 55.87; H, 3.62; N, 5.92.Found: C, 55.84; H, 3.61; N, 5.82.

EXAMPLE 3612-(3-Chlorophenyl)-4-[2-(methylpropyl)thiol]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 359,substituting 2-methyl-1-propanethiol in place of benzyl mercaptan(yield: 0.134 g, 91%). Oil. ¹H NMR (300 MHz, DMSO d₆) δ 0.61 (d, J=6 Hz,6H), 1.54-1.69 (m, 1H), 2.91 (d, J=6 Hz, 2H), 3.33 (s, 3H), 7.52-7.64(m, 3H), 7.74 (m, 1H), 7.79 (m, 2H), 8.04 (m, 3H). MS (DCI/NH₃) m/z 449(M+H)⁺, 466 (M+NH₄)⁺. Anal. calc. for C₂₁H₂₁ClN₂O₃S₂ (0.50H₂O): C,55.07; H, 4.84; N, 6.11. Found: C, 54.70; H, 4.64; N, 5.85.

EXAMPLE 3622-(3-Chlorophenyl)-4-(cyclopentyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

To a −78° C. solution of2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone,prepared in Example 333, (0.175 g, 0.33 mmol) in THF (3.3 mL) was addedcyclopentyl magnesium chloride (0.17 mL, 1.0 M in diethyl ether). Theresulting solution was stirred under nitrogen less than 1 hour withwarming to room temperature. The reaction was poured into water andextracted with ethyl acetate. The combined organics were dried overMgSO₄ and concentrated in vacuo. The resulting crude product waspurified using flash chromatography (SiO₂, 2:1 ethyl acetate:hexanes) toprovide the desired product (yield: 0.1328 g, 94%). mp 155-157° C. ¹HNMR (300 MHz, DMSO d₆) δ 1.50 (m, 2H), 1.66 (m, 2H), 1.79 (m, 2H), 2.09(m, 2H), 2.90 (m, J=8 Hz, 1H), 3.26-3.37 (3H, obstructed by H₂O),7.49-7.63 (m, 3H), 7.71 (m, 3H), 7.97 (s, 1H), 8.10 (m, 2H). MS(DCI/NH₃) m/z 429 (M+H)⁺, 446 (M+NH₄)⁺. Anal. calc. for C₂₂H₂₁ClN₂O₃S:C, 61.60; H, 4.93; N, 6.53. Found: C, 61.48; H, 4.81; N, 6.22.

EXAMPLE 3632-(3-Chlorophenyl)-4-(2-methylpropyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound, an oil, was prepared according to the method ofExample 362, substituting isobutyl magnesium chloride in place ofcyclopentylmagnesium chloride, (yield: 0.132 g, 96%). ¹H NMR (300 MHz,CDCl₃) δ 0.77 (d, J=6 Hz, 6H), 2.08 (m, 1H), 2.54 (d, J=7 Hz, 2H),7.36-7.46 (m, 2H), 7.56 (m, 2H), 7.62 (m, 1H), 7.73 (m, 2H), 8.11 (m,2H). MS (DCI/NH₃) m/z 417 (M+H)⁺ 434 (M+NH₄)⁺. Anal. calc. forC₂₁H₂₁ClN₂O₃S.0.50H₂O: C, 59.21; H, 5.20; N, 6.57. Found: C, 59.27; H,5.40; N, 6.12.

EXAMPLE 3642-(3-Chlorophenyl)-4-(cyclopentylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound, an oil, was prepared according to the method ofExample 362, substituting cyclopentylmethyl magnesium bromide in placeof cyclopentyl magnesium chloride (yield: 0.0579 g, 38%). ¹H NMR (300MHz, DMSO d₆) δ 0.66 (m, 2H), 1.03 (m, 3H), 1.50 (m, 6H), 1.61 (m, 1H),2.46 (m, 1H), 3.27-3.42 (3H, obstructed by H₂O), 7.50-7.66 (m, 3H), 7.75(m, 3H), 7.99 (s, 1H), 8.10 (m, 2H). MS (DCI/NH₃) m/z 457 (M+H)⁺, 474(M+NH₄)⁺. Anal. calc. for C₂₄H₂₅ClN₂O₃S: C, 63.08; H, 5.51; N, 6.13.Found: C, 63.08; H, 5.47; N, 6.04.

EXAMPLE 3652-(3-Chlorophenyl)-4-(2-cyclopentylethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 362,substituting cyclopentylethyl magnesium bromide in place of cyclopentylmagnesium chloride (yield: 0.165 g, 94%). H NMR (300 MHz, DMSO d₆) δ0.76 (m, 3H), 0.99-1.21 (m, 5H), 1.31-1.62 (m, 8H), 2.42-2.56 (1H,obstructed by DMSO), 3.25-3.34 (2H, obstructed by H₂O), 7.48-7.65 (m,3H), 7.48-7.65 (m, 3H), 7.76 (m, 3H), 8.01 (s, 1H), 8.10 (m, 2H). MS(DCI/NH₃) m/z 471 (M+H)⁺, 488 (M+NH₄)⁺. Anal. calc. for C₂₅H₂₇ClN₂O₃S:C, 63.75; H, 5.78; N, 5.95. Found: C, 63.48; H, 5.70; N, 5.67.

EXAMPLE 3662-(3-Chlorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 362,substituting 3-methylbutyl magnesium bromide in place ofcyclopentylmagnesium chloride (yield: 0.0221 g, 16%). mp 60-65° C. ¹HNMR (300 MHz, DMSO d₆) δ 0.75 (d, J=7 Hz, 6H), 1.32-1.52 (m, 3H), 3.31(s, 3H), 7.50-7.65 (m, 3H), 7.77 (m, 3H), 8.03 (s, 1H), 8.11 (m, 2H). MS(DCI/NH₃) m/z 431 (N+H)⁺, 448 (M+NH₄)⁺. Anal. calc. forC₂₂H₂₃ClN₂O₃S.0.25H₂O: C, 60.68; H, 5.43; H, 6.43. Found C, 60.29; H,5.60; N, 6.17.

EXAMPLE 3672-(3-Chlorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 362,substituting benzyl magnesium chloride in place of cyclopentylmagnesiumchloride. mp 174-177° C. (yield: 25.9 g, 57%). ¹H NMR (300 MHz, DMSO d₆)δ 3.30 (s, 3H), 3.91 (bs, 2H), 7.02 (m, 2H), 7.12-7.25 (m, 3H),7.51-7.64 (m, 3H), 7.72 (m, 3H), 8.07 (m, 2H), 8.12 (s, 1H). MS(DCI/NH₃) m/z 451 (M+H)⁺, 468 (+N)⁺. Anal. calc. for C₂₄H₁₉ClN₂O₃S: C,63.92; H, 4.25; N, 6.21. Found: C, 63.69; H, 4.28; N, 6.02.

EXAMPLE 3682-(3-Chlorophenyl)-4-cyclohexyl-5-[4-(ethylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 362substituting cyclohexylmagnesium chloride in place ofcyclopentylmagnesium chloride (yield: 0.099 g, 68%). mp 85-90° C. ¹H NMR(300 M, CDCl₃) δ 1.01-1.30 (m, 3H), 1.48-1.69 (m, 3H), 1.75 (m, 2H),2.28 (m, 2H), 2.57 (m, 1H), 3.16 (s, 3H), 7.35-7.46 (m, 2H), 7.50-7.62(m, 3H), 7.68 (m, 2H), 8.11 (m, 2H). MS (DCI/NH₃) m/z 443 (M+H)⁺, 460(M+NH₄)⁺. Anal. calc. for C₂₃H₂₃ClN₂O₃S (1.25H₂O): C, 59.34; H, 5.52; N,6.01. Found: C, 59.02; H, 5.24; N, 5.65.

EXAMPLE 3692-(3-Chlorophenyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228using the product from Example 207C and substituting 4-fluorobenzylmagnesium chloride in place of cyclohexyl magnesium chloride (yield:0.1895 g, 41%). mp 183-185° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.25-3.36(3H, obstructed by H₂O), 3.89 (bs, 2H), 6.97-7.09 (m, 4H), 7.50-7.64 (m,3H), 7.71 (m, 3H), 8.06 (m, 2H), 8.11 (s, 1H). MS (DCI/NH₃) m/z 469(M+H)⁺, 486 (M+NH₄)⁺. Anal. calc. for C₂₄H₈ClFN₂O₃S: C, 61.47; H, 3.87;N, 5.97. Found: C, 61.23; H, 3.84; N, 5.77.

EXAMPLE 3702-(3-Chlorophenyl)-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 362substituting p-tolylmagnesium bromide in place of cyclopentylmagnesiumchloride (yield: 65 mg, 40.9%). mp 222-224° C. ¹H NMR (300 MHz, DMSO-d₆)δ 2.28 (s, 3H), 3.25 (s, 3H), 7.12 (t, 4H), 7.6 (m, 5H), 7.79 (t, 1H)7.9 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (DCI/NH₃) m/z 451 (M+H)⁺, 468(M+NH₄)⁺. Anal. calc. for C₂₄H₁₉ClN₂O₃S.0.25H₂O: C, 63.92; H, 4.25; N,6.21. Found: C, 62.99; H, 4.28; N, 5.85.

EXAMPLE 3712-(3,4-Difluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-(3,4-Difluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonewas prepared according to the method of Example 362, starting with2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand substituting 3-fluoro-4-methylphenylmagnesium bromide in place ofcyclopentylmagnesium chloride to provide the methyl sulfide compound.

The methyl sulfide was oxidized according to the method of Example 10 toprovide the title compound (yield: 265 mg, 85.4%). mp 204-206° C. ¹H NMR(300 MHz, CDCl₃) δ 2.25 (br s, 3H), 3.08 (s, 3H), 6.83 (dd, J=9 Hz, 1.5Hz, 1H), 6.96 (dd, J=9 Hz, 1.5 Hz, 1H), 7.08 (t, J=9 Hz, 1H), 7.23-7.33(m, 1H), 7.41 (d, J=9 Hz, 2H), 7.49-7.56 (m, 1H), 7.61-7.69 (m, 1H),7.93 (d, J=9 Hz, 2H), 7.99 (s, 1H). MS (DCI/NH₃) m/z 471 (M+H)⁺, 488(M+NH₄)⁺. Anal. calc. for C₂₄H₁₇F₃N₂O₃S: C, 61.28; H, 3.62; N, 5.96.Found: C, 61.07; H, 3.95; N, 5.56.

EXAMPLE 3722-(3-Chlorophenyl)-4-(phenethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,starting with2-(3-chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneand substituting phenethyl magnesium chloride in place ofcyclohexylmagnesium chloride then oxidizing by the method of Example 10(yield: 0.100 g, 39%). mp 142-145° C. ¹H NMR (300 MHz, DMSO d₆) δ 2.80(m, 4H), 3.30 (s, 3H), 7.01 (m, 2H), 7.21 (m, 3H), 7.51-7.60 (m, 4H),7.63 (m, 1H), 7.78 (m, 1H), 8.03 (m, 3H). MS (DCI/NH₃) m/z 465 (M+H)⁺,482 (M+NH₄). Anal. calc. for C₂H₂₁ClN₂O₃S: C, 64.58; H, 4.55; N, 6.02.Found: C, 64.24; H, 4.50; N, 5.90.

EXAMPLE 3732-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(methylsulfonyl)phenyl]3(2H)-pyridazinoneEXAMPLE 373A2-(3-Chloro-phenyl)-4-(2-methylpropoxy)-5-bromo-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 194B,starting with 2-(3-chlorophenyl)-4,5-dibromo-3(2H)-pyridazinone (Example207A) in place of 2-(4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone andsubstituting 2-methyl-1-propanol in place of methanol.

EXAMPLE 373B2-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 6,starting with2-(3-chlorophenyl)-4-(2-methylpropoxy)-5-bromo-3(2H)-pyridazinone inplace of 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone and substituting3-fluoro-4-(methylthio)benzeneboronic acid (Example 72D) in place of4-fluorobenzeneboronic acid.

EXAMPLE 373C2-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

Example 373B was oxidized according to the method of Example 10 TOprovide the title compound (yield: 0.73 g, 100%). mp 180-183° C. ¹H NMR(300 MHz, DMSO d₆) δ 0.82 (d, J=6 Hz, 2H), 3.30-3.39 (3H, obstructed byH₂O) 4.25 (d, J=6 Hz, 2H), 7.57 (m, 3H), 7.75 (m, 1H), 7.85 (m, 1H),8.00 (m, 1H), 8.23 (s, 1H). MS (DCI/NH₃) m/z 451 (M+H)⁺, 468 (M+NH₄)⁺.Anal. calc. for C₂₁H₂₀ClFN₂O₄S: C, 55.94; H, 4.47; N, 6.21. Found: C,55.73; H, 4.58; N, 6.01.

EXAMPLE 3742-(3-Chlorophenyl)-4-(benzyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

To a stirred solution of2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 332) (0.100 g, 0.28 mmol) in DMF (2.8 mL) was added benzylchloride (6.32 mL, 0.28 mmol). The resulting solution was stirred withheating to 60° C. overnight. The solvent was removed in vacuo and theresulting residue partitioned between ethyl acetate and 10% citric acid.After extracting with ethyl acetate, the combined organics were driedover MgSO₄ and concentrated in vacuo. The crude product was purifiedusing flash chromatography (SiO₂, 1:1 ethyl acetate:hexanes) to providethe desired product (yield: 0.096 g, 76%). mp 110-113° C. ¹H NMR (300MHz, DMSO d₆) δ 3.39 (s, 3H), 5.48 (s, 2H), 7.29 (m, 4H), 7.59-7.71 (m,3H), 7.76 (m, 3H), 8.00 (m, 2H), 8.21 (s, 1H). MS (DCI/NH₃) m/z 467(M+H)⁺, 484 (M+NH₄)⁺. Anal. calc. for C₂₄H₁₉ClN₂O₄S: C, 61.73; H, 4.10;N, 6.00. Found: C, 62.00; H, 4.18; N, 5.93.

EXAMPLE 3752-(4-Fluorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

2-(4-Fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone (Example 194B)was converted into2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneaccording to the method of Example 194C followed by the oxidation methodin Example 10. The methoxy compound was converted to the2-(4-fluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone,by treatment with NaOH according to the procedure of Example 332. Thehydroxy compound was treated with p-toluenesulfonyl chloride accordingto the procedure of Example 333, to furnish2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone.

The title compound was prepared according to the method of Example 335,starting with2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinonein place of2-(3-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-0.3(2H)-pyridazinone substituting 3-methyl-1-butanol in place of isobutanol(yield: 0.3932 g, 94%). mp 117-120° C. ¹H NMR (300 MHz, DMSO d₆) δ 0.79(d, J=6 Hz, 6H), 1.41-1.59 (m, 3H), 3.30 (s, 3H), 4.42 (d, J=5 Hz, 2H),7.36 (m, 2H), 7.65 (m, 2H), 7.90 (m, 2H), 8.06 (m, 2H), 8.18 (s, 1H). MS(DCI/NH₃) m/z 431 (M+H)⁺, 448 (M+NH₄)⁺. Anal. calc. for C₂₂H₂₃FN₂O₄S: C,61.38; H, 5.39; N, 6.51. Found: C, 61.42; H, 5.30; N, 6.40.

EXAMPLE 3762-(4-Fluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared-according to the method of Example 335,substituting2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone(prepared as an intermediate in Example 375) in place of2-(3-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone(yield: 0.486 g, 100%). mp 121-128° C. ¹H NMR (300 MHz, DMSO d₆) δ 0.78(d, J=7 Hz, 6H), 1.84 (m, 1H), 3.30 (s, 3H), 4.20 (d, J=6 Hz, 2H), 7.37(m, 2H), 7.66 (m, 2H), 7.92 (m, 2H), 8.07 (m, 2H), 8.19 (s, 1H). MS(DCI/NH₃) m/z 417 (M+H)⁺, 434 (M+NH₄)⁺. Anal. calc. forC₂₁H₂₁FN₂O₄S.0.50H₂O: C, 59.28; H, 5.21; N, 6.58. Found: C, 59.49; H,4.97; N, 6.34.

EXAMPLE 3772-(4-Fluorophenyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 62,starting with4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand reacting with 1-iodo-4-fluorobenzene (yield: 0.0881 g, 78%). mp175-177° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.27-3.36 (3H, obstructed byH₂O), 3.88 (bs, 2H), 6.98-7.09 (m, 4H), 7.34 (m, 2H), 7.65 (m, 2H), 7.71(m, 2H), 8.06 (m, 3H). MS (DCI/NH₃) m/z 453 (M+H)⁺, 470 (M+NH₄)⁺. Anal.calc. for C₂₄H₁₈F₂N₂O₃S: C, 63.71; H, 4.01; N, 6.19. Found: C, 63.61; H,4.26; N, 6.03.

EXAMPLE 3782-(4-Fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,substituting 3-methylbutyl magnesium bromide in place ofcyclohexylmagnesium chloride (yield: 0.325 g, 69%). mp 151-154° C. ¹HNMR (300 MHz, DMSO d₆) δ 0.75 (d, J=7 Hz, 6H), 1.32-1.51 (m, 3H), 3.31(s, 3H), 7.37 (m, 2H), 7.66 (m, 2H), 7.77 (m, 2H), 8.00 (s, 1H), 8.10(m, 2H). MS (DCI/NH₃) m/z 415 (M+H)⁺, 432 (M+NH₄)⁺. Anal. calc. forC₂₂H₂₃FN₂O₃S.0.50H₂O: C, 62.39; H, 5.71; N, 6.61. Found: C, 62.04; H,5.78; N, 6.46.

EXAMPLE 3792-(Tetrahydro-2H-pyrano-2-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

To the solution of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneprepared according to Example 11 (172 mg, 0.5 mmol) andp-toluenesulfonic acid hydrate (19 mg, 0.1 mmol) in dioxane (10 mL) wasadded 2,3-dihydropyran (2 mL). The mixture was stirred at roomtemperature for 6 hours. The mixture was then poured into a solution ofsaturated NaHCO₃ and extracted with ethyl acetate. The ethyl acetate wasconcentrated in vacuo and the residue was chromatographed (silica gel,1:1 hexanes-ethyl acetate) to provide the title compound (yield: 25 mg,11%). ¹H NMR (DMSO-d₆, 300 MHz) δ 1.54 (m, 2H), 1.74 (m, 2H), 2.00 (m,1H), 2.17 (m, 1H), 3.23 (s, 3H), 3.62 (m, 1H), 4.00 (m, 1H), 5.98 (m,1H), 7.13 (7, J=9 Hz, 2H), 7.23 (m, 2H), 7.47 (d, J=9 Hz, 2H), 7.86 (d,J=9 Hz, 2H), 8.12 (s, 1H). MS (DCI/NH₃) m/z 429 (M+H)⁺.

EXAMPLE 3802-(3-(4-Fluorophenyl)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 4,starting with2-(3-bromophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 166) in place of2-benzyl-4-bromo-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone andsubstituting cesium fluoride for sodium carbonate (yield: 0.62 g, 62%).mp 222-225° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.24 (s, 3H), 7.16 (m, 2H),7.36 (m, 3H), 7.53 (m, 2H), 7.64 (m, 2H), 7.73-7.81 (m, 3H), 7.93 (m,3H), 8.27 (s, 1H). MS (DCI/NH₃) m/z 515 (M+H)⁺, 532 (M+NH₄)⁺. Anal.calc. for C₂₉H₂₀F₂N₂O₃S.0.25H₂O: C, 67.10; H, 3.98; N, 5.35. Found:C_(1-66.93); H, 3.99; N, 5.17.

EXAMPLE 3812-(2,2,2-Trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

2-(2,2,2-Trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinonewas prepared according to the method of Example 261, substituting2-(2,2,2-trifluoroethyl)-4-chloro-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinonein place of2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

The methyl sulfide was oxidized with one equivalent ofmeta-chloroperoxybenzoic acid to give the methyl sulfoxide. Thesulfoxide was converted to the title compound according to the method ofExample 68 (yield: 196 mg, 28%). mp 144-145° C. ¹H NMR (300 MHz, CDCl₃)δ 0.86 (s, 9H), 4.23 (s, 2H), 4.82 (q, J=8 Hz, 2H), 5.10 (s, 2H), 7.46(s, 1H), 7.48 (br s, 1H), 7.79 (s, 1H), 8.03 (t, J=8 Hz, 1H). MS(DCI/NH₃) m/z 438 (M+H)⁺. Anal. calc. for C₁₇H₁₉F₄N₃O₄S: C, 46.68; H,4.38; N, 9.61. Found: C, 46.76; H, 4.30; N, 9.52.

EXAMPLE 3822-(2,2,2-Trifluoroethyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 68substituting2-(2,2,2-trifluoroethyl)-4-(2-methylpropoxy)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinonein place of2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone(yield: 260 mg, 26%). mp 163-164° C. ¹H NMR (300 MHz, CDCl₃) δ 0.86 (d,J=6.6 Hz, 6H), 1.91 (septet, J=6.6 Hz, 1H), 4.34 (d, J=6.6 Hz, 2H), 5.11(br s, 2H), 7.43-7.52 (m, 2H), 7.80 (s, 1H), 8.02 (t, J=8 Hz, 1H). MS(DCI/NH₃) m/z 424 (M+H)⁺, m/z 441 (M+NH₄)⁺. Anal. calc. forC₁₆H₁₇F₄N₃O₄S: C, 45.39; H, 4.05; N, 9.92. Found: C, 59.89; H, 3.83; N,8.61.

EXAMPLE 3832-Benzyl-4-(4-fluorobenzyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 384,substituting2-benzyl-4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3,4-difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 0.5723 g 34%). mp 120-123° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.83(bs, 2H), 5.30 (bs, 2H), 6.95-7.06 (m, 4H), 7.28-7.40 (m, 5H), 7.48 (m,2H), 7.60 (m, 2H), 7.91 (m, 2H), 7.95 (s, 1H). MS (DCI/NH₃) m/z 450(M+H)⁺, 467 (M+NH₄)⁺. Anal. calc. for C₂₄H₂₀FN₃O₃S: C, 64.13; H, 4.48;N, 9.35. Found: C, 63.76; H, 4.71; N, 9.02.

EXAMPLE 3842-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

To a solution of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(130 mg, 0.3 mmol) and di-t-butylazodicarboxylate (DBAD) (69 mg, 0.3mmol) in THF (30 mL) at −78° C. was added dropwise a 1 N solution oflithium 1,1,1,3,3,3-hexamethyldisilazide (0.9 mL, 0.9 mmol) in THF

After addition, the reaction was stirred an additional 45 minutes at−78° C. (or until the TLC indicated a disappearance of startingmaterial). The reaction was quenched with a saturated solution of NH₄Cland extracted with ethyl acetate. The acetate extract was dried overMgSO₄ and concentrated in vacuo to obtain 220 mg of crude adduct.

The above adduct was dissolved in THF (30 mL) and was treated at roomtemperature with 1 N NaOH (3 mL) for 5 hours. Sodium acetate(NaOAc.3H₂O, 1.38 g, 10 mmol) was added followed by addition ofhydroxylamine-O-sulfonic acid (1.13 g, 10 mmol) and H₂O (30 mL). Theresulting mixture was stirred at room temperature for 18 hours and thenextracted with ethyl acetate. The extract was washed with water, brine,dried over MgSO₄ and concentrated in vacuo. The residue was purified bychromatography (silica gel, 1:1 hexanes-ethyl acetate) to provide thedesired product (yield: 70 mg, 54%). mp 185-189° C. ¹H NMR (DMSO-d₆, 300MHz) δ 5.33 (s, 2H), 7.11 (m, 2H), 7.22 (m, 2H), 7.40 (m, 7H), 7.83 (d,J=9 Hz, 2H), 8.10 (s, 1H). MS (DCI/NH₃) m/z 436 (M+H)⁺. Anal. calc. forC₂₃H₁₈N₃O₃S.0.75H₂O: C, 61.65; H, 4.26; N, 9.04. Found: C, 61.67; H,4.61; N, 8.66.

EXAMPLE 3852-(4-Fluorophenyl)-4-(4-fluorophenoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The product from Example 108 was converted to the title sulfonamideaccording to the method of Example 384, (yield: 65 mg, 28.8%). mp227-229° C. ¹H NMR (300 MHz, DMSO-d₆) δ 7.08-7.17 (m, 4H), 7.36 (t, J=3Hz, 2H), 7.47 (br s, 2H), 7.61-7.69 (m, 2H), 7.83 (d, J=9 Hz, 2H), 7.93(d, J=9 Hz, 2H), 8.40 (s, 1H). MS (DCI/NH₃) m/z 469 (M+H)⁺, 486(M+NH₄)⁺. Anal. calc. for C₂₄H₁₅F₂N₃O₄S: C, 58.02; H, 3.30; N, 9.24.Found: C, 57.84; H, 3.34; N, 9.01.

EXAMPLE 3862-(3,4-Difluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The product from Example 371 was converted to the title sulfonamideaccording to the method of Example 384 (yield: 45 mg, 28%). mp 198-200°C. ¹H NMR (300 MHz, DMSO-d₆) δ 6.87 (dd, J=9 Hz, 3 Hz, 1H), 7.13 (dt,J=9 Hz, 3 Hz, 1H), 7.19 (t, J=7 Hz, 1H), 7.46 (d, J=9 Hz, 2H), 7.47 (brs, 2H), 7.52-7.69 (m, 2H), 7.79 (d, J=9 Hz, 2H), 7.82-7.89 (m, 1H), 8.25(s, 1H). MS (DCI/NH₃) m/z 472 (M+H)⁺, 489 (M+NH₄)⁺.

EXAMPLE 3872-(4-Fluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The product from Example 250 was converted to the title sulfonamideaccording to the method of Example 384 (yield: 185 mg, 46%). mp 187-188°C. ¹H NMR (300 MHz, DMSO-d₆) δ 2.22 (br s, 3H), 6.87 (dd, J=9 Hz, 3 Hz,1H), 7.16 (q, J=9 Hz, 2H), 7.38 (t, J=9 Hz, 2H), 7.46 (br s, 2H), 7.47(d, J=9 Hz, 2H), 7.67-7.73 (m, 2H), 7.77 (d, J=9 Hz, 2H), 8.22 (s, 1H).MS (DCI/NH₃) m/z 454 (M+H)⁺, 471 (M+NH₄)⁺. Anal. calc. forC₂₃H₁₇F₂N₃O₃S.0.25H₂O: C, 60.36; H, 3.87; N, 9.19. Found: C, 60.30; H,4.26; N, 8.83.

EXAMPLE 3882-(3,4-Difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)pyridazinone

The product from Example 109 was converted to the title sulfonamideaccording to the method of Example 384 (yield: 110 mg, 45.7%). mp224-226° C. ¹H NMR (300 MHz, CDCl₃) δ 4.86 (br s, 2H), 6.89-7.03 (m,4H), 7.19-7.30 (m, 1H), 7.45-7.52 (m, 1H), 7.56-7.66 (m, 1H), 7.79 (d,J=9 Hz, 2H), 8.04 (d, J=9 Hz, 1H), 8.08 (s, 1H). MS (DCI/NH₃) m/z 474(M+H)⁺, 491 (M+NH₄)⁺. Anal. calc. for C₂₂H₁₄F₃N₃O₄S.0.25H₂O: C, 55.32;H, 2.93; N, 8.80. Found: C, 55.26; H, 3.11; N, 8.58.

EXAMPLE 3892-(3-Chloro-4-fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The product from Example 247 was converted to the title sulfonamideaccording to the method of Example 384 (yield: 230 mg, 38%). mp 243-245°C. ¹H NMR (300 MHz, DMSO-d₆) δ 2.17 (br s, 3H), 6.94-7.09 (m, 2H), 7.25(dd, J=9 Hz, 3 Hz, 1H), 7.41-7.48 (m, 4H), 7.60 (t, J=9 Hz, 1H),7.68-7.75 (m, 1H), 7.77 (d, J=9 Hz, 2H), 7.95 (dd, J=6 Hz, 3 Hz, 1H),8.25 (s, 1H). MS (DCI/NH₃) m/z 469 (M+H)⁺, 486 (M+NH₄)⁺. Anal. calc. forC₂₃H₁₆ClF₂N₃O₃S: C, 56.67; H, 3.29; N, 8.63: Found: C, 56.81; H, 3.35;N, 8.95.

EXAMPLE 3902-(4-Fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The methyl sulfone product of Example 245 was converted to the titlesulfonamide according to the method of Example 384 (yield: 78 mg,28.3%). mp 202-204° C. ¹H NMR (300 MHz, CDCl₃) δ 2.22 (s, 3H), 4.86 (s,2H), 6.83-6.91 (m, 2H), 7.14-7.25 (m, 3H), 7.36 (d, J=9 Hz, 2H),7.65-7.72 (m, 2H), 7.91 (d, J=9 Hz, 2H), 8.0 (s, 1H). MS (DCI/NH₃) m/z454 (M+H)⁺, 471 (M+NH₄)⁺. Anal. calc. for C₂₃H₁₇F₂N₃O₃S.0.25H₂O: C,60.36; H, 3.77; N, 9.19. Found: C, 60.24; H, 3.93; N, 9.25.

EXAMPLE 3912-(3-Chlorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The methyl sulfone product of Example 244 was converted to the titlesulfonamide according to the method of Example 384 (yield: 125 mg, 39%).mp 187-188° C. ¹H NMR (300 MHz, CDCl₃) δ 2.21 (s, 3H), 4.71 (s, 2H),6.85-6.92 (m, 2H), 7.21 (d, J=9 Hz, 1H), 7.32-7.47 (m, 2H), 7.37 (d, J=9Hz, 2H), 7.64 (dt, J=7 Hz, 3 Hz, 1H), 7.77 (br s, 1H), 7.91 (d, J=9 Hz,2H). MS (DCI/NH₃) m/z 470 (M+H)⁺, 487 (M+NH₄)⁺. Anal. calc. forC₂₃H₁₇ClFN₃O₃S.0.25H₂O: C, 58.32; H, 3.65; N, 8.88., Found: C, 58.27; H,3.91; N, 8.62.

EXAMPLE 3922-(3-Chloro-phenyl)-4-(3-methylbutyl)-5-[4-(aminosulfonyl)phenyl]-(2H)-pyridazinone

The title compound was prepared according to the method of Example 384,substituting2-(3-chlorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 366) in place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 0.0756 g, 16%). mp 167-170° C. ¹H NMR (300 MHz, DMSO d₆) δ 0.78(d, J=6 Hz, 6H), 1.47 (5H, obstructed by hexanes), 7.51-7.65 (m, 4H),7.68 (m, 2H), 7.75 (m, 1H), 7.98 (m, 2H), 8.03 (s, 1H), 8.60 (bs, 1H).MS (DCI/NH₃) m/z 432 (M+H)⁺, 449 (M+NH₄)⁺. Anal. calc. for C₂₁H₂₂ClN₃O₃S(0.25H₂O): C, 57.79; H, 5.19; N, 9.62. Found: C, 57.78; H, 5.02; N,9.40.

EXAMPLE 3932-(3-Chlorophenyl)-4-(phenethyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 384,substituting2-(3-chlorophenyl)-4-(phenethyl)-5-[4-(methylsulfonyl)phenyl]-3-(2H)-pyridazinone(Example 372) in place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 0.075 g, 17%). semi-solid; ¹H NMR (300 MHz, DMSO d₆) δ 2.80 (m,4H), 3.29-3.42 (3H, obstructed by H₂O), 6.96 (m, 2H), 7.14-7.28 (m, 3H),7.46-7.68 (m, 7H), 7.78 (m, 1H), 7.92 (m, 2H), 8.01 (s, 1H). MS(DCI/NH₃) m/z 466 (M+H)⁺, 483 (M+NH₄). Anal. calc. forC₂₄H₂₀ClN₂O₃S.0.25H₂O: C, 61.27; H, 4.39; N, 8.93. Found: 61.18; H,4.68; N, 8.58.

EXAMPLE 3942-(3-Chlorophenyl)-4-(3-methylbutoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 384,substituting2-(3-chlorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 339) in place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 0.575 g, 18%). mp 137-139° C. ¹H NMR (300 MHz, DMSO d₆) δ 0.81(d, J=7 Hz, 6H), 1.49 (m, 2H), 1.57 (m, 1H), 4.42 (t, J=7 Hz, 2H),7.44-7.65 (m, 5H), 7.76 (m, 1H), 7.84 (m, 2H), 7.94 (m, 2H), 8.20 (s,1H). MS (DCI/NH₃) m/z 448 (M+H)⁺, 465 (M+NH₄)⁺. Anal. calc. forC₂₁H₂₂ClN₃O₄S: C, 56.31; H, 4.95; N, 9.38. Found C, 56.02; H, 4.82; N,9.31.

EXAMPLE 3952-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 384,substituting2-(3-chlorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 335) in place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 0.0458 g, 25%). mp 80-85° C. ¹H NMR (300 MHz, DMSO (16) δ 0.80(d, J=6 Hz, 6H), 1.74-1.92 (m, 3H), 4.20 (d, J=6 Hz, 2H), 7.49-7.64 (m,SH), 7.76 (m, 1H), 7.85 (m, 2H), 7.95 (m, 2H), 8.21 (m, 1H). MS(DCI/NH₃) m/z 434 (M+H)⁺, 451 (M+NH₄)⁺. Anal. calc. for C₂₀H₂₀ClN₃O₄S:C, 55.36; H, 4.65; N, 9.68. Found: C, 55.12; H, 4.58; N, 9.42.

EXAMPLE 3962-(4-Fluorophenyl)-4-(3-methylbutyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 384,substituting2-(4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 378) in place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(0.090 g 21%). mp 180-183° C. ¹H NMR (300 MHz, DMSO d₆) δ 0.78 (d, J=6Hz, 6H), 1.49 (m, 5H), 7.36 (m, 2H), 7.53 (m, 2H), 7.62-7.73 (m, 4H),7.98 (m, 3H). MS (DCI/NH₃) m/z 416 (M+H)⁺, 433 (M+NH₄)⁺. Anal. calc. forC₂₁H₂₂FN₃O₃S: C, 60.71; H, 5.34; N, 10.11. Found: C, 60.37, H, 5.36; N,9.84.

EXAMPLE 3972-(4-Fluorophenyl)-4-(2-methylpropoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 384,substituting2-(4-fluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 376) in place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 0.024 g, 6%). mp 132-136° C. ¹H NMR (300 MHz, DMSO d₆) δ 0.79(d, J=6 Hz, 6H), 1.83 (m, 1H), 4.19 (d, J=6 Hz, 2H), 7.36 (m, 2H), 7.50(m, 2H), 7.66 (m, 2H), 7.84 (m, 2H), 7.95 (m, 2H), 8.18 (s, 1H). MS(DCI/NH₃) m/z 418 (M+H)⁺, 435 (M+NH₄)⁺. Anal. calc. for C₂₀H₂₀FN₃O₄S: C,57.54; H, 4.83; N, 10.07. Found C, 57.26; H, 5.00; N, 9.78.

EXAMPLE 3982-(4-Fluorophenyl)-4-(3-methylbutoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 384,substituting2-(4-fluorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 375) in place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 0.051 g, 18%). Yellow oil. ¹H NMR (300 MHz, DMSO d₆) δ 0.80 (d,J=5 Hz, 6H), 1.47 (m, 3H), 4.42 (t, J=6 Hz, 2H), 7.37 (m, 2H), 7.50 (m,1H), 7.65 (m, 2H), 7.83 (m, 2H), 7.93 (m, 2H), 8.18 (s, 1H), 8.60 (bs,1H). MS (DCI/NH₃) m/z 432 (M+H)⁺, 449 (M+NH₄)⁺. Anal. calc. forC₂₁H₂₂FN₃O₄S: C, 58.46; H, 5.14; N, 9.74. Found: C, 58.16; H, 5.21; N,9.57.

EXAMPLE 3992-(t-Butyl)-4-(3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

2-(t-Butyl)-4-(3-methyl-1-butoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneprepared in Example 330C. was oxidized with one equivalent ofmeta-chloroperoxybenzoic acid to the corresponding methyl sulfoxide. Thesulfoxide was converted to the title sulfonamide by the method ofExample 68 (yield: 1.25 g, 54%). mp 153-155° C. ¹H NMR (300 MHz, CDCl₃)δ 0.82 (d, J=6 Hz, 2H), 1.48 (q, J=6 Hz, 2H), 1.49-1.69 (m, 1H), 1.70(s, 9H), 4.37 (t, J=6 Hz, 2H), 4.32 (s, 2H), 7.70 (d, J=9 Hz, 2H), 7.72(s, 1H), 8.01 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 394 (M+H)⁺. Anal. calc.for C₁₉H₂₇N₃O₄S: C, 57.99; H, 6.91; N, 10.67. Found: C, 58.11; H, 6.71;N, 10.58.

EXAMPLE 4002-(3,4-Difluoro-phenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to Example 384 substituting2-(3,4-difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 182) in place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 950 mg, 54%). mp 177-181° C. ¹H NMR (300 MHz, DMSO-d₆) δ 7.15(t, 2H), 7.29 (m, 2H), 7.43 (s, 1H), 7.45 (bs, 2H), 7.59 (m, 2H), 7.76(d, J=9 Hz, 2H), 7.85 (m, 1H), 8.27 (s, 1H). MS (DCI/NH₃) m/z 458(M+H)⁺, 475 (M+NH₄)⁺. Anal. calc. for C₂₂H₁₄F₃N₃O₃S: C, 57.77; H, 3.08;N, 9.19. Found, C, 57.22; H, 3.28; N, 8.99.

EXAMPLE 4012-(3-Chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 384,substituting2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 380 mg, 47%). mp 208-210° C. ¹H NMR (300 MHz, DMSO-d₆) 8.7.15(t, 2H), 7.27 (m, 2H), 7.43 (s, 1H), 7.45 (bs, 2H) 7.51 (d, J=9 Hz, 4H),7.6 (t, 1H), 7.7 (m, 1H), 7.75 (d, J=9 Hz, 2H), 7.94 (dd, 1H), 8.25 (s,1H). MS (DCI/NH₃) m/z 474 (M+H)⁺, 491 (M+NH₄)⁺. Anal. calc. forC₂₂H₁₄F₂Cl₂N₃O₃S.0.5H₂O: C, 55.76; H, 2.98; N, 8.87. Found: C, 56.05; H,3.42; N, 8.65.

EXAMPLE 4022-(3,4-Difluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)—pyridazinone

The title compound was prepared according to the method of procedureExample 384, substituting2-(3,4-difluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 105 mg, 27%). mp 243-245° C. ¹H NMR (300 MHz, DMSO-d₆) δ 2.2 (s,3H), 7.01 (m, 2H), 7.25 (m, 1H), 7.45 (s, 1H), 7.47 (bs, 2H), 7.6 (m,2H), 7.77 (d, J=9 Hz, 2H), 7.85 (m, 1H), 8.26 (s, 2H). MS (DCI/NH₃) m/z472 (M+H)⁺, 489 (M+NH₄)⁺. Anal. calc. for C₂₄H₁₇F₃N₂O₃S.0.5H₂O: C,58.59; H, 3.42; N, 8.91. Found: C, 57; H, 4.23; N, 8.89.

EXAMPLE 4032-(3,4-Difluorophenyl)-4-(2-methylpropoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 384,substituting2-(3,4-difluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 35 mg, 42%). mp 169-171° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.78 (d,6H), 1.84, (m, 1H), 4.2 (d, 2H), 7.54 (m, 3H), 7.6 (m, 1H), 7.82 (m,3H), 7.91 (d, 2H), 8.21 (s, 1H). MS (DCI/NH₃) m/z 436 (M+H)⁺, 453(M+NH₄)⁺. Anal. calc. for C₂₀H₁₉F₂N₃O₄S.0.25H₂O: C, 55.17; H, 4.40; N,9.65. Found: C, 54.19; H, 4.25; N, 9.35

EXAMPLE 4042-(3,4-Difluorophenyl)-4-(3-methylbutyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 384,substituting2-(3,4-difluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 58 mg, 52%). mp 171-173° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.75 (d,6H), 1.4, (m, 3H), 2.48 (m, 2H), 3.3 (s, 3H), 7.51 (m, 1H), 7.65 (m,1H), 7.75 (d, J=9 Hz, 2H), 7.81 (m, 1H) 8.05 (s, 1H), 8.12 (d, J=9 Hz,2H). MS (DCI/NH₃) M/z 434 (M+H)⁺, 451 (M+NH₄)⁺. Anal. calc. forC₂₁H₂₁F₂N₃O₃S.0.25H₂O: C, 58.19; H, 4.88; N, 9.69. Found: C, 57.69; H,5.01; N, 9.18.

EXAMPLE 4052-(3-Chloro-4-fluoro-phenyl)-4-(3-methylbutyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 384,substituting2-(3-chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 102 mg, 61.8%). mp 154-156° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.75(d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 7.54 (s, 2H), 7.6 (m, 1H), 7.69 (m,2H), 7.93 (dd, 1H), 8.05 (m, 2H). MS (DCI/NH₃) m/z 450 (M+H)⁺, 468(M+NH₄)⁺. Anal. calc. for C₂₂H₂₂FN₂O₃SCl.0.25H₂O: C, 58.86; H, 4.94; N,6.24. Found: C, 59.23; H, 5.12; N, 6.00.

EXAMPLE 4062-(3,4-Difluorophenyl)-4-(2,2-dimethylpropoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 384substituting2-(3,4-difluorophenyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 310 mg, 38%). mp 173-175° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.8 (s,9H), 3.3 (s, 3H), 4.1 (s, 2H), 7.51 (m, 3H), 7.6 (m, 1H), 7.85 (m, 3H),7.95 (d, J=9 Hz, 2H), 8.21 (s, 1H). MS (DCI/NH₃) m/z 450 (M+H)⁺, 467(M+NH₄)⁺. Anal. calc. for C₂₁H₂₁F₂N₃O₄S: C, 56.12; H, 4.71; N, 9.35.Found, C, 55.83; H, 4.73; N, 9.08.

EXAMPLE 4072-(3,4-Difluorophenyl)-4-(4-fluorophenoxy)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 384substituting2-(3,4-difluorophenyl)-4-(4-fluorophenoxy)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 125 mg, 31%). mp 224-226° C. ¹H-NMR (300 MHz, DMSO-d₆) δ 7.15(d, 4H), 7.51 (m, 1H), 7.6 (m, 2H) 7.75 (m, 4H), 7.9 (t, 1H); 8.4 (s,1H). MS (DCI/NH₃) m/z 492 (M+H)⁺, 509 (M+NH₄)⁺. Anal. calc. forC₂₂H₁₃F₄N₃O₄S: C, 53.77; H, 2.67; N, 8.55. Found; C, 53.33; H, 2.84; N,8.22

EXAMPLE 4082-(3,3-Difluoro-2-propenyl)₁₋₄-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The intermediate,2-benzyl-4-(4-fluorophenyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinoneprepared according to the method of Example 72, was oxidized with oneequivalent of meta-chloroperoxybenzoic acid to provide the methylsulfoxide which was converted to the sulfonamide according to the methodof Example 68. The sulfonamide material was N-debenzylated according tothe method of Example 11 and N-alkylated according to the method ofExample 20, substituting 1,3-dibromo-1,1-difluoropropane in place of4-fluorobenzyl bromide and employing 4 equivalents of potassiumcarbonate to provide the title compound (yield: 120 mg, 27%). mp180-183° C. ¹H NMR (300 MHz, CDCl₃) δ 4.71 (dt, J=15 Hz, 7.5 Hz, 2H),4.75 (d, J=7.5 Hz, 2H), 5.06 (s, 2H), 7.02 (m, 2H), 7.19 (dd, J=9 Hz, 6Hz, 2H), 7.81 (s, 1H), 7.87 (t, J=7.5 Hz, 2H). MS (DCI/NH₃) Ml/Z 440(M+H)⁺. Anal. calc. for C₁₉H₁₃F₄N₃O₃S: C, 51.93; H, 2.98; N, 9.56.Found: C, 51.71; H, 3.15; N, 9.28.

EXAMPLE 4092-(3,4-Difluorophenyl)-4-[2-(2-propoxy)ethoxy]-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 384,substituting2-(3,4-difluorophenyl)-4-[2-(2-propoxy)ethoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 110 mg, 34%). mp 54-56° C. ¹H NMR 300 MHz, DMSO-d₆) δ 1.0 (d,6H), 3.43 (m, 1H), 3.54 (m, 2H), 4.63 (m, 2H), 7.5 (m, 3H), 7.6 (m, 1H),7.8 (m, 1H), 7.95 (m, 4H), 8.2 (s, 1H). MS (DCI/NH₃) m/z 466 (M+H)⁺, 483(M+NH₄)⁺. Anal. calc. for C₂₁H₂₁F₂N₃O₅S: C, 54.19; H, 4.55; N, 9.03.Found, C, 54.29; H, 4.67; N, 8.95.

EXAMPLE 4102-(3,4-Difluorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 384substituting2-(3,4-difluorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.mp 70-73° C. ¹H NMR (300 MHz, DMSO-d₆) δ 1.5 (d, 6H), 2.27 (m, 2H) 4.43(t, 2H), 4.5 (m, 1H), 7.5 (m, 2H), 7.6 (m, 1H), 7.8 (m, 2H), 7.92 (d,J=2H, 2H), 8.2 (s, 1H). MS (DCI/NH₃) m/z 462 (M+H)⁺, 479 (M+NH₄)⁺. Anal.calc. for C₂₂H₂₁F₂N₃O₄S: C, 57.26; H, 4.59; N, 9.11. Found: C, 56.96; H,4.70; N, 9.01.

EXAMPLE 4112-(3-Chlorophenyl)-4-(3-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting 3-fluorophenol in place of isobutanol (yield: 0.034 g,22%). mp 178-180° C. ¹H NMR (300 MHz, DMSO d₆) δ 3.27 (s, 3H), 6.88-7.00(m, 2H), 7.10 (m, 1H), 7.36 (m, 1H), 7.59 (m, 3H), 7.74 (m, 1H), 7.90(m, 2H), 8.06 (m, 2H), 8.43 (s, 1H). MS (DCI/NH₃) m/z 488 (M+H)⁺. Anal.calc. for C₂₃H₁₆ClFN₂O₄S.0.25H₂O: C, 58.10; H, 3.49; N, 5.89. Found C,58.04; H, 3.59; N, 5.80.

EXAMPLE 4122-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 384,substituting2-(3-chlorophenyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 0.019 g, 10%). mp 157-159° C. ¹H NMR (300 MHz, DMSO d₆) δ 0.81(d, J=6 Hz, 6H), 1.86 (m, 1H), 4.24 (d, J=6Hz, 2H), 7.75 (m, 3H), 7.66(m, 1H), 7.73 (m, 2H), 7.83 (m, 2H), 7.91 (m, 1H), 8.23 (s, 1H). Anal.calc. for C₂₁H₁₉ClFN₃O₄S: C, 53.16; H, 4.24; N, 9.30. Found: C, 53.02;H, 4.43; N, 9.10.

EXAMPLE 4132-(3-Chlorophenyl)-4-(4-methylpentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting 4-methyl-1-pentanol in place of isobutanol (yield: 0.137 g,90%). mp 139-140 IC. ¹H NMR (300 MHz, DMSO d₆) δ 0.74 (d, J=6 Hz, 6H),1.03 (m, 2H), 1.39 (m, 1H), 1.54 (m, 2H), 3.29 (s, 3H), 4.40 (t, J=5 Hz,2H), 7.51-7.60 (m, 3H), 7.75 (m, 1H), 7.90 (m, 2H), 8.07 (m, 2H), 8.20(s, 1H). MS (DCI/NH₃) m/z 461 (M+H)⁺, 478 (M+NH₄)⁺. Anal. calc. forC₂₃H₂₅ClN₂O₄S: C, 59.95; H, 5.97; N, 6.08. Found: C, 59.62; H, 5.63; N,5.86.

EXAMPLE 4142-(4-Fluorophenyl)-4-(4-methyl-pentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,starting with2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand substituting 4-methyl-1-pentanol in place of isobutanol (yield:0.128 g, 85%). mp 123-125° C. ¹H NMR (300 MHz, DMSO d₆) δ 0.74 (d, J=6Hz, 6H), 1.03 (m, 2H), 1.39 (m, 1H), 1.54 (m, 2H), 3.28 (s, 3H), 4.39(t, J=6 Hz, 2H), 7.37 (m, 2H), 7.66 (m, 2H), 7.91 (ha, 2H), 8.07 (m,2H), 8.18 (s, 1H). MS (DCI/NH₃) m/z 445 (M+H)⁺. Anal. calc. forC₂₃H₂₅FN₂O₄S: C, 62.14; H, 5.67; N, 6.30. Found: C, 62.28; H, 5.59; N,6.25.

EXAMPLE 4152-(4-Fluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 332,substituting2-(4-fluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonefor2-(3-chlorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 2.022 g, 97%). ¹H NMR (300 MHz, DMSO d₆) δ 3.28 (s, 3H), 7.38(m, 2H), 7.70 (m, 2H), 8.03 (m, 4H), 8.22 (s, 1H). MS (APCI−+Q1MS) 361(M+H)⁺, (−Q1MS) 359 (M−H).

EXAMPLE 4162-(4-Fluorophenyl)-4-cyclopropylmethoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand substituting cyclopropylmethanol in place of isobutanol (yield:0.117 g, 83%). mp 166-167° C. ¹H NMR (300 MHz, DMSO d₆) δ 0.22 (m, 2H),0.46 (m, 2H), 1.10 (m, 1H), 3.31 (s, 3H), 4.30 (d, J=7 Hz, 2H), 7.36 (m,2H), 7.66 (m, 2H), 7.96 (m, 2H), 8.07 (m, 2H), 8.20 (s, 1H). MS(DCI/NH₃) m/z 415 (M+H)⁺, 432 (M+NH₄)⁺. Anal. calc. for C₂₃H₂₅ClN₂O₄S:C, 60.86; H, 4.62; N, 6.76. Found: C, 60.76; H, 4.72; N, 6.61.

EXAMPLE 4172-(4-Fluorophenyl)-4-(2-cyclopropyl-1-ethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand substituting 2-cyclopropane ethanol in place of isobutanol (yield:0.1472 g, 100%). mp 111-117° C. ¹H NMR (300 MHz, DMSO d₆) δ −0.01 (m,2H), 0.31 (m, 2H), 0.60 (m, 1H), 1.49 (q, J=6 Hz, 2H), 3.29 (s, 3H),4.48 (t, J=6 Hz, 2H), 7.37 (m, 2H), 7.65 (m, 2H), 7.91 (m, 2H), 8.06 (m,2H), 8.17 (s, 1H). MS (DCI/NH₃) m/z 429 (M+H)⁺, 446 (M+NH₄)⁺. Anal.calc. for C₂₂H₂₁FN₂O₄S: C, 61.67; H, 4.94; N, 6.54. Found: C, 61.59; H,5.02; N, 6.45.

EXAMPLE 4182-(3-Chlorophenyl)-4-cyclopropanemethoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting cyclopropane methanol in place of isobutanol (yield: 0.0917g, 64%). mp 158-161° C. ¹H NMR (300 MHz, DMSO d₆) δ 0.22 (m, 2H), 0.46(m, 2H), 1.13 (m, 1H), 3.31 (s, 3H), 4.31 (d, J=7 Hz, 2H), 7.57 (m, 3H),7.75 (m, 1H), 7.96 (m, 2H), 8.08 (m, 2H), 8.23 (s, 1H). MS (DCI/NH₃) m/z431 (M+H)⁺, 448 (M+NH₄)⁺. Anal. calc. for C₂₁H₁₉ClN₂O₄S.0.25H₂O: C,57.92; H, 4.51; N, 6.43. Found: C, 57.86; H, 4.35; N, 6.27.

EXAMPLE 4192-(3-Chlorophenyl)-4-(2-cyclopropane-1-ethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting 2-cyclopropane ethanol in place of isobutanol (yield: 0.114g, 78%). mp 124-128° C. ¹H NMR (300 MHz, DMSO d₆) δ 0.00 (m, 2H), 0.32(m, 2H), 0.61 (m, 1H), 1.49 (q, J=6 Hz, 2H), 3.30 (s, 3H), 4.50 (t, J=6Hz, 2H), 7.58 (m, 3H), 7.76 (m, 1H), 7.91 (m, 2H), 8.07 (m, 2H), 8.21(s, 1H). MS (DCI/NH₃) m/z 445 (M+H)⁺, 462 (M+NH₄)⁺. Anal. calc. forC₂₂H₂₁ClN₂O₄S: C, 59.39; H, 4.76; N, 6.30. Found: C, 58.92; H, 4.94; N,6.15.

EXAMPLE 4202-(4-Fluorophenyl)-4-(4-methylpentyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 362,substituting2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand substituting 4-methylpentane-1-magnesium bromide for cyclopentylmagnesium chloride (yield: 0.165 g, 99%). mp 112-115° C. ¹H NMR (300MHz, DMSO d₆) δ 0.75 (d, J=7 Hz, 6H), 1.07 (q, J=7 Hz, 2H), 1.32-1.53(m, 3H), 2.45 (t, 2H), 3.31 (s, 3H), 7.37 (m, 2H), 7.66 (m, 2H), 7.76(m, 2H), 8.00 (s, 1H), 8.10 (m, 2H). MS (DCI/NH₃) m/z 429 (M+H)⁺. 446(M+NH₄)⁺. Anal. calc. for C₂₃H₂₅FN₂O₃S: C, 64.47; H, 5.88; N, 6.54.Found: C, 64.44; H, 5.90; N, 6.49.

EXAMPLE 4212-(3-Chlorophenyl)-4-(4-methylpentyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 362,substituting 4-methylpentane-1-magnesium bromide in place of cyclopentylmagnesium chloride (yield: 165 mg, 98%). oil. ¹H NMR (300 MHz, DMSO d₆)δ 0.76 (d, J=6 Hz, 6H), 1.07 (m, 2H), 1.33-1.55 (m, 3H), 2.45 (m, 2H),3.32 (s, 3H), 7.51-7.65 (m, 4H), 7.76 (m, 2H), 8.03 (s, 1H), 8.11 (m,2H). MS (DCI/NH₃) m/z 445 (M+H)⁺, 462 (M+NH₄)⁺. Anal. calc. forC₂₃H₂₅ClN₂O₃S: C, 62.06; H, 5.66; N, 6.30. Found: C, 61.86; H, 5.64; N,6.18.

EXAMPLE 4222-(4-Fluorophenyl)-4-(3-methyl-2-butenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand substituting 3-methyl-2-buten-1-ol in place of isobutanol (yield:0.1284 g, 88%). mp 128-132° C. ¹H NMR (300 MHz, DMSO d₆) δ 1.58 (s, 3H),1.67 (s, 3H), 3.30 (s, 3H), 4.95 (d, J=7 Hz, 2H), 5.31 (m, 1H), 7.38 (m,2H), 7.65 (m, 2H), 7.89 (m, 2H), 8.06 (m, 2H), 8.18 (s, 1H). MS(DCI/NH₃) m/z 429 (M+H)⁺, 446 (M+NH₃)⁺. Anal. calc. for C₂₂H₂₁FN₂O₄S: C,61.67; H, 4.94; N, 6.54. Found: C, 61.41; H, 4.95; N, 6.47.

EXAMPLE 4232-(3-Chlorophenyl)-4-(3-methyl-2-butenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone

The title compound was prepared according to the method of Example 335,substituting 3-methyl-2-buten-1-ol in place of isobutanol (yield: 0.119g, 81%). mp 113-115° C. ¹H NMR (300 MHz, DMSO d₆) δ 1.58 (s, 3H), 1.67(s, 3H), 3.31 (s, 3H), 4.96 (m, 2H), 5.32 (m, 1H), 7.58 (m, 3H), 7.75(m, 1H), 7.89 (m, 2H), 8.07 (m, 2H), 8.21 (s, 1H). MS (APCI+Q1MS) 445(M+H)⁺, (APCI−Q1MS) 479 (M+35)⁻. Anal. calc. for C₂₂H₂₁ClN₂O₄S: C,59.39; H, 4.76; N, 6.30. Found: C, 59.14; H, 4.66; N, 6.16.

EXAMPLE 4242-(4-Fluorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand substituting 4-methyl-3-penten-1-ol in place of isobutanol (yield:0.1165 g, 77%). mp 111-114° C. ¹H NMR (300 MHz, DMSO d₆) δ 1.46 (s, 3H),1.56 (s, 3H), 2.26 (m, 2H), 3.30 (s, 1H), 4.43 (t, J=7 Hz, 2H), 4.96 (m,1H), 7.37 (m, 2H), 7.65 (m, 2H), 7.91 (m, 2H), 8.06 (m, 2H), 8.18 (s,1H). MS (DCI/NH₃) m/z 443 (M+H)⁺, 460 (M+NH₄)⁺. Anal. calc. forC₂₃H₂₃FN₂O₄S: C, 62.43; H, 5.24; N, 6.33. Found: C, 62.32; H, 5.30; N,6.25.

EXAMPLE 425 2(4-Fluorophenyl)-4-(3-methyl-3-butenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand substituting 3-methyl-3-butene-1-ol in place of isobutanol (yield:0.1327 g, 91%). mp 109-111° C. ¹H NMR (300 MHz, DMSO d₆) δ 1.61 (s, 3H),2.32 (t, J=7 Hz, 2H), 3.30 (s, 3H), 4.56 (t, J=7 Hz, 2H), 4.63 (bs, 1H),4.68 (bs, 1H), 7.37 (m, 2H), 7.66 (m, 2H), 7.90 (m, 2H), 8.05 (m, 2H),8.19 (s, 1H). MS (DCI/NH₃) m/z 429 (M+H)⁺, 446 (M+NH₄)⁺. Anal. calc. forC₂₂H₂₁FN₂O₄S: C, 61.67; H, 4.94; N, 6.54. Found: C, 61.50; H, 5.00; N,6.45.

EXAMPLE 4262-(3-Chlorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone

The title compound was prepared according to the method of Example 335,substituting 4-methyl-3-pentene-1-ol in place of isobutanol (yield:0.1149 g, 76%). mp 110-111° C. ¹H NMR (300 MHz, DMSO dr) δ 1.47 (s, 3H),1.55 (s, 3H), 2.27 (m, 2H), 3.30 (s, 3H), 4.44 (t, J=6 Hz, 2H), 4.96 (m,1H), 7.52-7.64 (m, 3H), 7.75 (m, 1H), 7.91 (M, 2H), 8.06 (m, 2H), 8.21(s, 1H). MS (DCI/NH₃) m/z 459 (M+H)⁺, 476 (M+NH₄)⁺. Anal. calc. forC₂₃H₂₃ClN₂O₄S: C, 60.19; H, 5.05; N, 6.10. Found: C, 60.06; H, 4.90; N,5.96.

EXAMPLE 4272-(3-Chlorophenyl)-4-(3-methyl-3-butenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 335,substituting 3-methyl-3-butene-1-ol in place of isobutanol (yield:0.1159 g, 79%). mp 110-112° C. ¹H NMR (300 MHz, DMSO d₆) δ 1.62 (s, 3H),2.32 (t, J=7 Hz, 2H), 3.30 (s, 3H), 4.57 (t, J=6 Hz, 2H), 4.63 (bs, 1H),4.68 (bs, 1H), 7.51-7.64 (m, 3H), 7.76 (m, 1H), 7.90 (m, 2H), 8.05 (m,2H), 8.21 (s, 1H). MS (DCI/NH₃) m/z 445 (M+H)⁺, 462 (M+NH₄)⁺. Anal.calc. for C₂₂H₂₁ClN₂O₄S: C, 59.39; H, 4.76; N, 6.30. Found: C, 59.27; H,4.68; N, 6.18.

EXAMPLE 4282-(4-Fluorophenyl)-4-(1,5-hexadienyl-3-oxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 178,substituting 1,5-hexadien-3-ol in place of 2-ethyl-1-hexanol (yield: 150mg, 85%). mp 104-105° C. ¹H NMR (300 MHz, DMSO-d₆) δ 2.42 (m, 2H), 3.30(s, 3H), 5.00 (m, 2H), 5.17 (m, 2H), 5.64 (m, 2H), 7.36 (t, J=9 Hz, 2H),7.64 (m, 2H), 7.92 (d, J=9 Hz, 2H), 8.06 (d, J=9 Hz, 2H), 8.19 (s, 1H).MS (APCI+) m/z 441 (M+H)⁺; (APCI−) m/z 475 (M+Cl)—. Anal. calc. forC₂₃H₂₁FN₂O₄S: C, 62.71; H, 4.80; N, 6.35. Found: C, 62.96; H, 4.93; N,5.85.

EXAMPLE 4292-(4-Fluorophenyl)-4-(5-methyl-2-hexyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 178,substituting 5-methyl-2-hexanol in place of 2-ethyl-1-hexanol (yield:150 mg, 82%). mp 102-103° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.73 (d, J=7Hz, 6H), 1.04 (m, 2H), 1.14 (d, J=7 Hz, 3H), 1.40 (m, 3H), 3.29 (s, 3H),5.12 (m, 1H), 7.36 (t, J=9 Hz, 2H), 7.66 (m, 2H), 7.92 (d, J=9 Hz, 2H),8.07 (d, J=9 Hz, 2H), 8.19 (s, 1H). MS (APCI+) m/z 459 (M+H)⁺; (APCI−)m/z 493 (M+Cl)⁻. Anal. calc. for C₂₄H₂₇FN₂O₄S: C, 62.86; H, 5.93; N,6.10. Found: C, 62.83; H, 5.99; N, 6.07.

EXAMPLE 4302-(4-Fluorophenyl)-4-(2-ethyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 178,substituting 2-ethyl-1-butanol in place of 2-ethyl-1-hexanol (yield: 140mg, 80%). mp 107-108° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.73 (t, J=7 Hz,6H), 1.20 (quintet, J=7 Hz, 4H), 1.40 (m, 1H), 3.29 (s, 3H), 4.29 (d,J=7 Hz, 2H), 7.37 (t, J=9 Hz, 2H), 7.66 (m, 2H), 7.90 (d, J=9 Hz, 2H),8.07 (d, J=9 Hz, 2H), 8.19 (s, 1H). MS (APCI+) m/z 445 (M+H)⁺; (APCI−)m/z 479 (M+Cl)⁻. Anal. calc. for C₂₃H₂₅FN₂O₄S: C, 62.14; H, 5.66; N,6.30. Found: C, 62.05; H, 5.86; N, 6.30.

EXAMPLE 4322-(4-Fluorophenyl)-4-(2-thioisopropyl-1-ethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 178,substituting 2-(isopropylthio)ethanol in place of 2-ethyl-1-hexanol(yield: 138 mg, 74%). mp 137-139° C. ¹H NMR (300 MHz, DMSO-d₆) δ 1.13(d, J=7 Hz, 6H), 2.77 (t, J=7 Hz, 2H), 2.88 (quintet, J=7 Hz, 1H), 3.29(s, 3H), 4.58 (t, J=7 Hz, 2H), 7.37 (t, J=9 Hz, 2H), 7.66 (m, 2H), 7.92(d, J=9 Hz, 2H), 8.06 (d, J=9 Hz, 2H), 8.18 (s, 1H). MS (APCI+) m/z 463(M+H)⁺. Anal. calc. for C₂₂H₂₃FN₂O₄S₂: C, 57.12; H, 5.01; N, 6.05.Found: C, 56.82; H, 4.91; N, 5.99.

EXAMPLE 4332-(4-Fluorophenyl)-4-(3-methylthio-1-hexyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 178,substituting 3-(methylthio)-1-hexanol in place of 2-ethyl-1-hexanol(yield: 155 mg, 79%). mp 90-92° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.78 (t,J=7 Hz, 3H), 1.30 (m, 4H), 1.76 (m, 2H), 2.82 (s, 3H), 2.38 (m, 1H),3.29 (s, 3H), 4.55 (m, 2H), 7.37 (t, J=9 Hz, 2H), 7.66 (m, 2H), 7.92 (d,J=9 Hz, 2H), 8.06 (d, J=9 Hz, 2H), 8.18 (s, 1H). MS (APCI+) m/z 491(M+H)⁺; (APCI−) m/z 525 (M+Cl)—. Anal. calc. for C₂₄H₂₇FN₂O₄S₂: C,58.75; H, 5.54; N, 5.70. Found: C, 58.66; H, 5.54; N, 5.66.

EXAMPLE 4342-(4-Fluorophenyl)-4-(2-methyl-4-pentenyl-1-oxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 178,substituting 2-methyl-4-penten-1-ol in place of 2-ethyl-1-hexanol(yield: 135 mg, 76%). mp 106-107° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.76(d, J=7 Hz, 3H), 1.78 (m, 2H), 2.00 (m, 1H), 3.29 (s, 3H), 4.25 (m, 2H),4.90 (m, 2H), 5.67 (m, 1H), 7.37 (t, J=9 Hz, 2H), 7.66 (m, 2H), 7.92 (d,J=9 Hz, 2H), 8.06 (d, J=9 Hz, 2H), 8.18 (s, 1H). MS (APCI+) m/z 443(M+H)⁺; (APCI−) m/z 477 (M+Cl)⁻. Anal. calc. for C₂₃H₂₃FN₂O₄S: C, 62.42;H, 5.23; N, 6.33. Found: C, 62.13; H, 5.12; N, 6.22.

EXAMPLE 4352-(3,4-Difluorophenyl)-4-(3-trifluoromethyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

To a solution of2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(189 mg, 0.5 mmol), Ph₃P (262 mg, 1 mmol) and3-trifluoromethyl-1-butanol (66 mg, 0.5 mmol) in THF (25 mL) was addeddropwise a solution of DIAD (0.2 mL, 1 mmol) in THF (5 mL) and theresulting mixture was stirred at room temperature for 8 hours. Themixture was concentrated in vacuo and the residue was chromatographed(silica gel, 1:1 hexanes-ethyl acetate) to provide the desired product,(yield: 180 mg 71%). mp 126-128° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.96 (d,J=7 Hz, 3H), 1.55 (m, 1H), 1.97 (m, 1H), 2.30 (m, 1H), 3.29 (s, 3H),4.46 (m, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz,2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 503 (M+H)⁺;(APCI−) m/z 537 (M+Cl)⁻. Anal. calc. for C₂₂H₁₉F₅N₂O₄S: C, 52.59; H,3.81; N, 5.57. Found: C, 52.70; H, 3.73; N, 5.63.

EXAMPLE 4362-(3,4-Difluorophenyl)-4-ethoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 178,starting with2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand substituting ethanol in place of 2-ethyl-1-hexanol (yield: 25 mg,12%). mp 121-123° C. ¹H NMR (300 MHz, DMSO-d₆) δ 1.23 (t, J=7 Hz, 3H),3.30 (s, 3H), 4.51 (q, J=7 Hz, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m,1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS(APCI+) m/z 407 (M+H)⁺; (APCI−) m/z 441 (M+Cl)—. Anal. calc. forC₁₉H₁₆F₂N₂O₄S.0.25H₂O: C, 55.53; H, 4.04; N, 6.81. Found: C, 55.58; H,4.21; N, 6.61.

EXAMPLE 4372-(3,4-Difluorophenyl)-4-(4-methyl-1-pentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 178,starting with2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand substituting 4-methyl-1-pentanol in place of 2-ethyl-1-hexanol(yield: 120 mg, 52%). mp 98-99° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.73 (d,J=7 Hz, 6H), 1.02 (m, 2H), 1.29 (m, 1H), 1.54 (m, 2H), 3.30 (s, 3H),4.40 (t, J=7 Hz, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d,J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 463(M+H)⁺; (APCI−) m/z 497 (M+Cl). Anal. calc. for C₂₃H₂₄F₂N₂O₄S: C, 59.72;H, 5.23; N, 6.05. Found: C, 59.57; H, 5.28; N, 6.01.

EXAMPLE 4382-(3,4-Difluorophenyl)-4-(4-methyl-2-pentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 178,starting with2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand substituting 4-methyl-2-pentanol for 2-ethyl-1-hexanol (yield: 115mg, 50%). mp 132-133° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.80 (d, J=7 Hz,3H), 0.87 (d, J=7 Hz, 3H), 1.10 (d, J=7 Hz, 3H), 1.26 (m, 1H), 1.50 (m,1H), 1.63 (m, 1H), 3.30 (s, 3H), 5.31 (m, 1H), 7.52 (m, 1H), 7.62 (m,1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s,1H). MS (APCI+) m/z 463 (M+H)⁺; (APCI−) m/z 497 (M+Cl)⁻. Anal. calc. forC₂₃H₂₄F₂N₂O₄S: C, 59.72; H, 5.23; N, 6.05. Found: C, 59.44; H, 5.26; N,5.99.

EXAMPLE 4392-(3,4-Difluorophenyl)-4-(2-cyclopentyl-1-ethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 178,starting with2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand substituting 2-cyclopentyl-1-ethanol in place of 2-ethyl-1-hexanol(yield: 115 mg, 60%). mp 100-101° C. ¹H NMR (300 MHz, DMSO-d₆) δ 1.00(m, 2H), 1.38 (m, 2H), 1.57 (m, 7H), 3.30 (s, 3H), 4.42 (t, J=7 Hz, 2H),7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d,J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 475 (M+H)⁺; (APCI−) m/z 509(M+Cl)⁻. Anal. calc. for C₂₄H₂₄F₂N₂O₄S.0.25H₂O: C, 60.17; H, 5.15; N,5.84. Found: C, 60.12; H, 5.14; N, 5.76.

EXAMPLE 4402-(3,4-Difluorophenyl)-4-(2-cyclopent-2-enyl-1-ethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 178,starting with2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand substituting 2-cyclopent-2-enyl-1-ethanol in place of2-ethyl-1-hexanol (yield: 95 mg, 48%). mp 126-127° C. ¹H NMR (300 MHz,DMSO-d₆) δ 1.30 (m, 1H), 1.57 (sextet, J=7 Hz, 1H), 1.69 (sextet, J=7Hz, 1H), 1.87 (m, 2H), 2.57 (m, 1H), 3.30 (s, 3H), 4.45 (m, 2H), 5.60(m, 1H), 5.68 (m, 1H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90(d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 473(M+H)⁺; (APCI−) m/z 507 (M+Cl)⁻. Anal. calc. for C₂₄H₂₂F₂N₂O₄S: C,61.00; H, 4.69; N, 5.92. Found: C, 60.76; H, 4.65; N, 5.80.

EXAMPLE 4412-(2-Hydroxy-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A mixture of the product from Example 46,2-phenacyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(700 mg, 1.5 mmol), and sodium borohydride (69 mg, 1.8 mmol) in ethanol(200 mL), was stirred at 40° C. for 2 hours. The reaction mixture wasthen concentrated in vacuo and the residue was partitioned between ethylacetate and 2 N aqueous hydrochloric acid. The organic layer was washedwith brine, dried over MgSO₄, and filtered. The filtrate wasconcentrated in vacuo to provide a pale yellow solid which wascrystallized from ethyl acetate/hexanes to provide the title compound aswhite crystals (yield: 540 mg, 78%). mp 205-207° C. ¹H NMR (300 MHz,CDCl₃) δ 3.07 (s, 3H), 3.75 (br s, 1H), 4.63-4.47 (m, 2H), 5.33 (dd, J=9Hz, 3 Hz, 1H), 7.00 (t, J=9 Hz, 2H), 7.20 (dd, J=9 Hz, 3 Hz, 2H),7.30-7.45 (m, 5H), 7.52 (d, J=9 Hz, 2H), 7.91 (s, 1H), 7.91 (d, J=9 Hz,2H). MS (DCI/NH₃) m/z 465 (M+H)⁺. Anal. calc. for C₂₅H₂₁FN₂O₄S: C,64.64; H, 4.55; N, 6.03. Found: C, 64.34; H, 4.66; N, 5.93.

EXAMPLE 4422-(2-Methoxy-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A mixture of the product from Example 441,2-(2-hydroxy-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(210 mg, 0.45 mmol), iodomethane (56 μL, 0.90 mmol), and an 80%0 oildispersion of sodium hydride (18 mg, 0.59 in mol) in anhydrous DMF (16mL) was stirred at room temperature for 18 hours. The reaction mixturewas partitioned between ethyl acetate and 2 N aqueous hydrochloric acid.The organic layer was washed with brine, dried over MgSO₄, and filtered.The filtrate was concentrated in vacuo to provide a yellow oil which waspurified by column chromatography (silica gel, 70:30 hexanes/ethylacetate). Fractions containing product were combined and concentrated invacuo, and the residue was triturated with hexanes to provide the titlecompound (yield: 75 mg, 34.7%). mp 135-137° C. ¹H NMR (300 MHz, CDCl₃) δ3.07 (s, 3H), 3.26 (s, 3H), 4.33-4.52 (m, 2H), 4.91 (dd, J=9 Hz, 3 Hz,1H), 6.99 (t, J=9 Hz, 2H), 7.20 (dd, J=9 Hz, 3 Hz, 2H), 7.31-7.50 (m,7H), 7.87 (s, 1H), 7.89 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 479 (M+H)⁺.Anal. calc. for C₂₆H₂₃FN₂O₄S: C, 65.25; H, 4.84; N, 5.85. Found: C,64.98; H, 4.83; N, 5.81.

EXAMPLE 4432-(2-Methoxyimino-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A mixture of the product from Example 46,2-phenacyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(220 mg, 0.476 mmol), methoxylamine hydrochloride (318 mg, 3.8 mmol),and sodium acetate (518 mg, 3.8 mmol) in methanol (100 mL) was stirredat reflux for 48 hours. The reaction mixture was concentrated in vacuo,and the residue was partitioned between ethyl acetate and saturatedaqueous ammonium chloride. The organic layer was washed with brine thendried over MgSO₄, and filtered. The filtrate was concentrated in vacuoto provide a brown oil which was purified by column chromatography(silica gel, 70:30 hexanes/ethyl acetate). Fractions containing productwere combined and concentrated in vacuo. The residue was crystallizedfrom methanol/water to provide the title compound as a mixture of E andZ oximes (yield: 82 mg, 35%). mp 95-99° C. ¹H NMR (300 MHz, CDCl₃) δ3.03 (s, 3H), 4.07 (s, 3H), 5.57 (s, 2H), 6.94 (t, J=9 Hz, 2H), 7.07(dd, J=9 Hz, 3 Hz, 2H), 7.24 (d, J=9 Hz, 2H), 7.31-7.37 (m, 3H),7.60-7.67 (m, 2H), 7.74 (s, 1H), 7.83 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z492 (M+H)⁺. Anal. calc. for C₂₆H₂₂FN₃O₄S: C, 63.53; H, 4.51; N, 8.54.Found: C, 63.40; Hi 4.51; N, 8.31.

EXAMPLE 4442-(3,4-Difluorophenyl)-4-(4-methylpentyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 255,substituting 1-bromo-4-methylpentane in place of 3,4-difluorobenzylbromide (yield: 145 mg, 58%). mp 111-113° C. ¹H NMR (300 MHz, DMSO-d₆) δ0.75 (d, 6H), 1.09 (m, 2H), 1.4 (m, 3H), 2.48 (m, 2H), 3.4 (s, 3H), 7.61(m, 2H), 7.75 (d, 2H), 7.81 (m, 1H), 8.02 (s, 1H), 8.1 (d, 2H). MS(DCI/NH₃) m/z 447 (M+H)⁺, 464 (M+NH₄)⁺. Anal. calc. for C₂₃H₂₄F₂N₂O₃S:C, 61.87; H, 5.42; N, 6.27. Found: C, 61.76; H, 5.55; N, 6.11.

EXAMPLE 4452-(3,4-Difluorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared as described in Example 384,substituting2-(3,4-difluorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 347) in place of2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 248 mg, 42%). mp 149-151° C. ¹H NMR (300 MHz, DMSO-d₆) δ 0.8 (d,J=6 Hz, 6H), 1.48 (m, 2H), 1.54 (m, 1H), 4.4 (t, 2H), 7.51 (m, 3H), 7.6(m, 1H), 7.85 (m, 3H), 7.95 (d, J=9 Hz, 2H), 8.21 (s, 1H). MS (DCI/NH₃)m/z 450 (M+H)⁺, 467 (M+NH₄)⁺. Anal. calc. for C₂₁H₂₁F₂N₃O₄S: C, 56.12;H, 4.71; N, 9.35. Found, C, 56.12; H, 4.67; N, 9.15.

EXAMPLE 4462-(2,2,2-Trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The intermediate,2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(m-ethylthio)phenyl]-3(2H)-pyridazinoneprepared in Example 9° C. was reacted with 2,2-dimethylpropanoyl toprovide2-(2,2,2-trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneaccording to the method of Example 90D.

The product was oxidized with one equivalent of meta-chloroperoxybenzoicacid to provide the methyl sulfoxide. The sulfoxide was converted to thetitle compound according to the method of Example 68, substituting2-(2,2,2-trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinonefor2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone(yield: 125 mg, 53%). mp 123-124° C. ¹H NMR (300 MHz, CDCl₃) δ 0.82 (s,9H), 4.18 (s, 2H), 4.82 (q, J=9 Hz, 2H), 4.84 (s, 2H), 7.70 (d, J=9 Hz,2H), 7.81 (s, 1H), 8.04 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 420 (M+H)⁺.Anal. calc. for C₁₇H₂₆F₃N₃O₄S: C, 48.68; Hi 4.80; N, 10.01. Found: C,48.76; H, 4.77; N, 9.94.

EXAMPLE 4472-(2,2,2-Trifluoroethyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 83,substituting 3-methyl-1-butanol in place of isopropanol (yield: 65 mg,85%). mp 111-113° C. ¹H NMR (300 MHz, CDCl₃) δ 0.84 (d, J=6 Hz, 6H),1.51 (m, 2H), 1.63 (m, 1H), 3.11 (s, 3H), 4.54 (t, J=6 Hz, 2H), 4.83 (q,J=9 Hz, 2H), 7.73 (d, J=9 Hz, 2H), 7.82 (s, 1H), 8.05 (d, J=9 Hz, 2H);MS (DCI/NH₃) m/z 419 (M+H)⁺. Anal. calc. for C₁₈H₂₁F₃N₂O₄S: C, 51.66; H,5.05; N, 6.69. Found: C, 51.91; H, 5.06; N, 6.56.

EXAMPLE 4482-(2,2,2-Trifluoroethyl)-4-(3-methylbutoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The intermediate,2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneprepared in Example 9° C. was reacted with 3-methyl-1-butanol to provide2-(2,2,2-trifluoroethyl)-4-(3-methylbutoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneaccording to the method of Example 90D.

The product was oxidized with one equivalent of meta-chloroperoxybenzoicacid to provide the methyl sulfoxide. The sulfoxide was converted to thetitle compound according to the method of Example 68, substituting2-(2,2,2-trifluoroethyl)-4-(3-methylbutoxy)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinonefor2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone(yield: 65 mg, 50%). mp 123-124° C.: ¹H NMR (300 MHz, CDCl₃) δ 0.84 (d,J=6 Hz, 6H), 1.52 (q, J=6 Hz, 2H), 1.60 (h, J=7.5 Hz, 1H), 4.52 (t, J=6Hz, 2H), 4.83 (q, J=9 Hz, 2H), 4.90 (s, 2H), 7.69 (d, J=9 Hz, 2H), 7.82(s, 1H), 8.04 (d, J=9 Hz, 2H). MS (DCI/NH₃) m/z 420 (M+H)⁺. Anal. calc.for C₁₇H₂₀F₃N₃O₄S: C, 48.68; H, 4.80; N, 10.01. Found: C, 48.86; H,4.83; N, 9.92.

EXAMPLE 4492-(2(2,2-Trifluoroethyl)-4-(2-methylpropoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The intermediate,2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneprepared in Example 9° C. was reacted with 2-methyl-1-propanol toprovide2-(2,2,2-trifluoroethyl)-4-(2-methylpropoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneaccording to the method of Example 90D.

The product was oxidized with one equivalent of meta-chloroperoxybenzoicacid to provide the methyl sulfoxide. The sulfoxide was converted to thetitle compound according to the method of Example 68, substituting2-(2,2,2-trifluoroethyl)-4-(2-methylpropoxy)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinonefor2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone(yield: 120 mg, 40%). mp 170-172° C. ¹H NMR (300 MHz, CDCl₃) δ 0.83 (d,J=6 Hz, 6H), 1.9 (m, 1H), 4.3 (m, 2H), 4.82 (s, 2H), 4.88 (m, 2H), 7.70(d, J=9 Hz, 2H), 7.79 (s, 1H), 8.03 (d, J=9 Hz, 2H); MS (DCI/NH₃) m/z406 (M+H)⁺. Anal. calc. for C₁₆H₁₈F₃N₃O₄S: C, 47.4; H, 4.47; N, 10.36.Found: C, 47.48; H, 4.36; N, 10.25.

EXAMPLE 4502-(2,3,3-Trifluoropropenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The product of Example4,2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,was N-debenzylated by the method of Example 11 to provide4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone. Theintermediate was mixed with one equivalent of1-methylsulfonyloxy-2,3,3-trifluoro-2-propene, (Example 88A) in ethylacetate, followed by one equivalent of cesium carbonate. The reactionmixture was heated to 50° C. for 5 hours. Aqueous work-up, followed bychromatography provided2-(2,3,3-trifluoropropenyl)-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(650 mg, 63%). The product was oxidized with one equivalent ofmeta-chloroperoxybenzoic acid to provide the methyl sulfoxide which wasconverted to the title compound according to the method of Example 68,substituting2-(2,3,3-trifluoropropenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinonefor2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone(yield: 65 mg, 35%). mp 190-193° C. ¹H NMR (300 MHz, CDCl₃) δ 5.07 (s,2H), 5.10 (dt, J=21 Hz, J=3 Hz, 2H), 7.05 (m, 4H), 7.19 (dd, J=9 Hz, J=6Hz, 2H), 7.84 (s, 1H), 7.87 (t, J=7.5 Hz, 1H). MS (ESI—NH₃) m/z 456(M−H)⁺. Anal. calc. for C₁₉H₁₂F₅N₃O₃S: C, 49.89; H, 2.64; N, 9.18.Found: C, 49.89; H, 2.73; N, 9.03.

EXAMPLE 4512-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 178,substituting 3-methyl-1,3-butanediol in place of 2-ethyl-1-hexanol(yield: 110 mg, 61%). mp 133-134° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 1.04(s, 6H), 1.72 (t, J=7 Hz, 2H), 3.29 (s, 3H), 4.32 (s, 1H), 4.53 (t, J=7Hz, 2H), 7.37 (t, J=9 Hz, 2H), 7.66 (m, 2H), 7.90 (d, J=9 Hz, 2H), 8.07(d, J=9 Hz, 2H), 8.19 (s, 1H); MS (APCI+) m/z 447 (M+H)⁺; (APCI−) m/z481 (M+Cl)⁻; Anal. calc. for C₂₂H₂₃FN₂O₅S-0.25H₂O: C, 58.59; H, 5.25; N,6.21. Found: C, 58.42; H, 5.00; N, 6.02.

EXAMPLE 4522-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 178,substituting2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand substituting 2-methyl-1,2-propanediol in place of 2-ethyl-1-hexanol(yield: 55 mg, 31%). ¹H NMR (300 MHz, DMSO-d₆) δ 0.97 (s, 6H), 3.30 (s,3H), 4.20 (s, 2H), 4.54 (s, 1H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m,1H), 7.98 (d, J=9 Hz, 2H), 8.05 (d, J=9 Hz, 2H), 8.21 (s, 1H); MS(APCI+) m/z 451 (M+H)⁺; (APCI−) m/z 485 (M+Cl)⁻; Anal. calc. forC₂₁H₂₀F₂N₂O₅S: C, 55.99; H, 4.47; N, 6.21. Found: C, 56.00; H, 4.48; N,5.87.

EXAMPLE 4532-(3,4-Difluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2)-pyridazinone

The title compound was isolated from the reaction mixture in Example233, as a product of oxidation of unreacted starting material (yield: 22mg, 8%). mp 113-115° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.3 (s, 3H), 4.1 (s,3H), 7.53 (m, 1H), 7.63 (m, 1H), 7.8 (m, 1H), 8.15 (d, 2H), 8.2 (s, 2H).MS (DCI/NH₃) m/z 393 (M+H)⁺, 410 (M+NH₄)⁺. Anal. calc. forC₁₈H₁₄F₂N₂O₄S: C, 55.10; H, 3.60; N, 7.14.

EXAMPLE 4542-(2,3,4,5,6-Pentafluorobenzyl)-4-(4-fluorophenyl)-5-[4-(dimethylamino)methylaminosulfonylphenyl]-3(2H)-pyridazinone

The title compound was isolated from the reaction mixture in Example125, as a product resulting from a reaction with the solvent,N,N-dimethylformamide (yield: 53 mg, 16%). mp 194-196° C. ¹H NMR (300MHz, CDCl₃) δ 3.05 (s, 3H), 3.17 (s, 3H), 5.49 (s, 2H), 6.97 (t, J=9 Hz,2H), 7.18 (dd, J=9 Hz, 6 Hz, 2H), 7.20 (d, J=9 Hz, 2H), 7.81 (s, —H),7.82 (d, J=9 Hz, 2H), 8.14 (s, 1H). MS (DCI/NH₃) m/z 581 (M+H)⁺. Anal.calc. for C₂₆H₁₈F₆N₄O₃S: C, 53.79; H, 312; N, 9.65. Found: C, 53.50; H,3.24; N, 9.56.

EXAMPLE 4552-(2,4-Difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(dimethylamino)methylaminosulfonylphenyl]-3(2H)-pyridazinone

The title compound was isolated from the reaction mixture in Example124, as a product resulting from a reaction with the solvent,N,N-dimethylformamide (yield: 55 mg, 18%). mp 193-195° C. ¹H NMR (300MHz, CDCl₃) δ 3.03 (s, 3H), 3.16 (s, 3H), 5.43 (s, 2H), 6.88 (m, 2H),6.95 (t, J=9 Hz, 2H), 7.18 (dd, J=9 Hz, 6 Hz, 2H), 7.20 (d, J=9 Hz, 2H),7.52 (m, 1H), 7.81 (d, J=9 Hz, 2H), 7.84 (s, 1H), 8.13 (s, 1H). MS(DCI/NH₃) m/z 527 (M+H)⁺. Anal. calc. for C₂H₂₁F₃N₄O₃S: C, 59.30; H,4.02; N, 10.64. Found: C, 59.08; H, 3.97; N, 10.48.

EXAMPLE 456(4-Fluorophenyl)-5-[4-(methylselenonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 456A 4-Bromoselenoanisole

Freshly crushed magnesium turnings (6.1 g, 0.25 mol) were suspended withvigorous stirring in a solution of diethyl ether (360 mL) and1,4-dibromobenzene (10 g, 0.04 mol). The solution was brought to refluxfor 30 minutes, without initiation. Several crystals of iodine wereadded which initiated the reaction to a self-sustained reflux. Thereflux was maintained as the remainder of the 1,4-dibromobenzene (49 g,0.21 mol) was slowly added. The reaction was refluxed for an additional2 hours after addition of the 1,4-dibromobenzene was completed. Whennearly all of the magnesium turnings had been consumed, the yellow/grayheterogeneous solution was cooled to 23° C., and selenium (19 g, 0.24mol) was added in small portions via spatula so as to maintain a gentlereflux. The selenium that became stuck to the sides of the flask waswashed in with additional diethyl ether. After addition, the solutionwas stirred for 20 minutes at 23° C. and then was cooled to 0° C. Adiethyl ether (20 mL) solution of methyl iodide (35.5 g, 0.25 mol) wasslowly added dropwise to the reaction mixture. Upon completion ofaddition, the cooling bath was removed, and the solution stirred for 3hours at 23° C. The reaction solution was slowly poured into ice water/1M HCl, and then the biphasic solution filtered through a glass woolplug. The ethereal layer was separated and the aqueous phase extractedtwice more with diethyl ether. The combined ethereal extracts were driedover MgSO₄, filtered, and concentrated in vacuo to provide asemi-viscous orange oil. On standing overnight at −20° C., large yellowneedles formed. The residual oil was drawn off via pipette to provide 17g (27%) of crystalline product. (J. Org. Chem., 1983, 48, 4169) ¹H NMR(300 MHz, CDCl₃) δ 2.46 (s, 3H), 7.12 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.7Hz, 2H). MS (APCI+) m/z 248 (Se₇₆ M+H)⁺, m/z 250 (Se₇₈ M+H)⁺, m/z 252(Se₈₀ M+H)⁺, and m/z 254 (Se₈₂ M+H)⁺.

EXAMPLE 456B2,4-Bis(4-fluorophenyl)-5-[4-(methylseleno)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 228,substituting2-(4-fluorophenyl)-4-methoxy-5-[4-(methylseleno)phenyl]-3(2H)-pyridazinone(prepared according to the method of Example 194C, substituting4-(methylseleno)benzeneboronic acid from Example 1 in place of4-(methylthio)benzeneboronic acid) in place of2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinoneand substituting 4-fluorophenyl magnesium bromide in place ofcyclohexylmagnesium chloride (yield: 44 mg, 69%). ¹H NMR (300 MHz,CDCl₃) δ 2.37 (s, 3H), 6.98 (dd, J=8.8, 8.8 Hz, 2H), 7.05 (d, J=8.7 Hz,2H), 7.17 (dd, J=8.7, 8.7 Hz, 2H), 7.23-7.31 (m, 2H), 7.32 (d, J=8.7 Hz,2H), 7.65-7.72 (m, 2H), 8.00 (s, 1H). MS (APCI+) m/z 455 (M+H)⁺.

EXAMPLE 456C2,4-Bis(4-fluorophenyl)-5-[4-(methylselenonyl)phenyl]-3(2H)-pyridazinone

A stirred solution of the2,4-bis(4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylseleno)phenyl]-3(2H)-pyridazinone(40 mg, 88.1 mmol) in methylene chloride (2 mL) was treated with3-chloroperoxybenzoic acid (100 mg, 342 mmol, 57-86%) at 23° C. After 2hours, the reaction appeared to be only slightly more than 50%completed. Additional 3-chloroperoxybenzoic acid (80 mg, 274 mmol,57-86%) was added. The reaction ran to completion over the next 16 hoursof stirring at 23° C. The solution was diluted with ethyl acetate andcarefully shaken with a NaHSO₃ solution (two times) for several minutesto consume the excess 3-chloroperoxybenzoic acid. The ethyl acetatesolution was subsequently washed with a saturated Na₂CO₃ solution (twotimes), water, and brine and dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was chromatographed (flash silicagel, acetone/methylene chloride/hexanes 2:2:1) to provide the product(yield: 40 mg, 93%). (J. Chem. Soc., Chem. Commun., 1985, 569). mp110-150° C. ¹H NMR (300 MHz, CDCl₃) δ 3.32 (s, 3H), 6.91 (dd, J=8.7, 8.7Hz, 2H), 7.14-7.27 (m, 4H), 7.48 (d, J=8.4 Hz, 2H), 7.65-7.73 (m, 2H),7.97 (s, 1H), 8.00 (d, J=8.4 Hz, 2H). MS (APCI+) m/z 487 (M+H)⁺ and m/z504 (M+NH₄)⁺. Anal. calc. for C₂₃H₁₆F₂N₂O₃Se.0.5H₂O: C, 55.88; H, 3.46;N, 5.66. Found: C, 55.60; H, 3.61; N, 5.29.

EXAMPLE 4572-(3,4-Difluorophenyl)-4-(3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared as described in Example 62, startingwith4-(3,4-difluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone andsubstituting 3,4-difluorobromobenzene in place of1-bromo-4-fluorobenzene (yield: 185 mg, 46.5%). mp 182-185° C. ¹H NMR(300 MHz, DMSO-d₆) δ 3.23 (s, 3H), 6.98 (d, J=9 Hz, 1H), 7.18 (m, 2H),7.32 (m, 1H), 7.52 (d, J=9 Hz, 2H), 7.6 (m, 2H), 7.85 (m, 1H), 7.9 (d,J=9 Hz, 2H), 8.3 (s, 1H). MS (DCI/NH₃) m/z 457 (M+H)⁺, 474 (M+NH₄)⁺.

EXAMPLE 4582-(4-Fluorophenyl)-4-(3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared as described in Example 62, substituting4-(3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone inplace of4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 135 mg, 34%). mp 199-201° C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.24(s, 3H), 6.98 (d, J=9 Hz, 1H), 7.18 (m, 2H), 7.32 (m, 1H), 7.39 (t, 1H),7.54 (d, J=9 Hz, 2H), 7.71 (m, 2H), 7.91 (d, J=9 Hz, 2H), 8.27 (s, 1H).MS (DCI/NH₃) m/z 439 (M+H)⁺, 456 (M+NH₄)⁺.

EXAMPLE 4592-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

To a solution of2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(139 mg, 0.309 mmol) and di-t-butylazodicarboxylate (71.2 mg, 0.309mmol) in THF (25 mL) at −78° C. was added dropwise a 1M solution ofNaHMDS (0.93 mL, 0.928 mmol) in THF. After addition the reaction wasstirred another 45 min at −78° C. (or until TLC indicated adisappearance of starting material) and then was treated with 1N NaOH(20 mL). The reaction mixture was stirred at room temperature for thenext 18 h. Sodium acetate trihydrate (758 mg, 5.57 mmol) was addedfollowed by addition of hydroxylamine-O-sulphonic acid (630 mg, 5.57mmol) and H₂O (50 mL). The resulting mixture was stirred at ambienttemperature for the next 18 hours and then extracted with EtOAc. Theextract was washed with water, brine, dried over MgSO₄ and concentratedin vacuo. The residue was purified by chromatography (silica gel, 1:1hexanes-EtOAc) to provide the title compound (yield: 25 mg; 18%). mp65-69° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 1.0 (s, 6H), 4.2 (s, 2H), 4.56(s, 1H), 7.51 (m, 3H), 7.6 (m, 1H), 7.85 (m, 1H), 7.95 (s, 4H), 8.21 (s,1H); MS (DCI/NH₃) m/z 451 (M+H)⁺, 467 (M+NH₄)⁺.

EXAMPLE 4602-(3,4-Difluorophenyl)-4-(2-oxo-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A solution of2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(378 mg, 1 mmol), Ph₃P (524 mg, 2 mmol) and acetol (74 mg, 1 mmol) inTHF (25 mL) at room temperature was treated dropwise with a solution ofDIAD (0.4 mL, 2 mmol) in THF (5 mL). The mixture was stirred at roomtemperature for 6 hours and concentrated in vacuo. The residue waschromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide thedesired product (yield: 205 mg, 48%). mp 169-170° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 2.08 (s, 3H), 3.30 (s, 3H), 5.30 (s, 2H), 7.48 (m, 1H), 7.62(q, J=10 Hz, 1H), 7.75 (m, AH), 7.94 (d, J=9 Hz, 2H), 8.05 (d, J=9 Hz,2H), 8.21 (s, 1H); MS (APCI+) m/z 435 (M+H)⁺, (APCI−) m/z 469 (M+Cl)—;Anal. calc. for C₂₀H₁₆F₂N₂O₅S-0.75H₂O: C, 53.62; H, 3.93; N, 6.25.Found: C, 53.26; H, 3.61; N, 6.08.

EXAMPLE 4612-(3,4-Difluorophenyl)-4-[2-(methoxyimino)-1-propoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A mixture of2-(3,4-difluorophenyl)-4-(2-oxo-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonefrom Example 460 (150 mg, 0.3 mmol) in H₂O (10 mL) and dioxane (20 mL)was treated with methoxyamine hydrochloride (84 mg, 1 mmol) and sodiumacetate trihydrate (138 mg, 1 mmol). The mixture was stirred at roomtemperature for 6 hours. The reaction mixture was extracted with ethylacetate and purified by column chromatography (silica gel, 1:1hexanes-ethyl acetate) to provide the title compound (yield: 20 mg,15%). mp 143-145° C.; ¹H NMR (300. MHz, DMSO-d₆) δ 1.63 (s, 3H), 3.30(s, 3H), 3.74 (s, 3H), 4.93 (s, 2H), 7.54 (m, 1H), 7.65 (q, J=10 Hz,1H), 7.82 (m, 1H), 7.92 (d, J=9 Hz, 2H), 8.07 (d, J=9 Hz, 2H), 8.24 (s,1H); MS (APCI+) m/z 464 (M+H)⁺; (APCI−) m/z 498 (M+Cl)—. Anal. calc. forC₂₁H₁₉F₂N₃OS: C, 54.42; H, 4.13; N, 9.06. Found: C, 54.33; H, 3.93; N,8.92.

EXAMPLE 462(S)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 462A (R)-3-t-Butoxy-2-methyl-1-propanol

A solution of (S)-(+)-methyl 3-hydroxy-2-methylpropionate (1.18 g, 10mmol) in t-butyl acetate (30 mL) was treated with 70% HClO₄ (0.1 mL) andthe reaction mixture was left at room temperature in a tightly closedflask for 24 hours. The mixture was then poured into a saturatedsolution of NaHCO₃ and extracted with ethyl ether. The ether was removedin vacuo and the residue was dissolved in THF (50 mL). To the resultingsolution was added NaBH₄ (925 mg, 25 mmol) and at 55° C. dropwisemethanol (10 mL). The reaction was continued at 55° C. for 1 hours, thenit was cooled to ambient temperature, acidified with 10% citric acid topH 5 and extracted with ethyl acetate. The acetate extract was washedwith water, brine, dried with MgSO₄ and concentrated in vacuo. Theresidue was chromatographed (silica gel, 2:1 hexane-ethyl acetate) toprovide (R)-3-t-butoxy-2-methyl-1-propanol (yield: 1 g, 68%). ¹H NMR(300 MHz, CDCl₃) δ 0.85 (d, J=7 Hz, 3H), 1.20 (s, 9H), 2.03 (m, 1H),3.30 (t, J=12 Hz, 1H), 3.53 (dd, J=4.5 Hz, 12 Hz, 1H), 3.70 (m, 2H); MS(DCI/NH₃) m/z 164 (M+NH₄)⁺.

EXAMPLE 462B(S)-2-(3,4-Difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-(4-methylsulfonyl)phenyl]-3(2H)-pyridazinone

To a solution2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl-3(2H)-pyridazinone(378 mg, 1 mmol), Ph₃P (524 mg, 2 mmol) and Example 462A (146 mg, 1mmol) in THF (25 mL) at room temperature was added dropwise a solutionof DIAD (0.4 μL, 2 mmol) in THF (5 μL). The mixture was then stirred atroom temperature for 6 hours and concentrated in vacuo. The residue waspassed through a silica gel pad (hexane-ethyl acetate as an eluent) toprovide 550 mg of roughly purified(S)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone,still contaminated with reduced DIAD. MS (APCI+) m/z 507 (M+H)⁺; (APCI−)m/z 541 (M+Cl)⁻.

EXAMPLE 462C(S)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A mixture of Example 462B (100 mg, ˜0.2 mmol) in TFA (5 mL) was left atambient temperature for 24 hours. The mixture was then concentrated invacuo, the residue was neutralized with saturated solution of NaHCO₃ andextracted with ethyl acetate. Purification on a column (silica gel, 1:2hexanes-EtOAc) gave a foamy product (yield: 51 mg, 56%). ¹H NMR (300MHz, DMSO-d₆) δ 0.75 (d, J=7 Hz, 3H), 1.81 (sextet (J=7 Hz, 1H), 3.21(d, J=6 Hz, 2H), 3.30 (s, 3H), 4.29 (dd, J=6 Hz, 12 Hz, 1H), 4.40 (dd,J=6 Hz, 12 Hz, 1H), 4.48 (br s, 1H), 7.52 (m, 1H), 7.61 (m, 1H), 7.80(m, 1H), 7.91 (d, J=9 Hz, 2H), 8.07 (d, J=9 Hz, 2H), 8.20 (s, 1H); MS(APCI+) m/z 451 (M+H)⁺; (APCI−) m/z 485 (M+Cl)-; Anal. calc. forC₂₁H₂₀F₂N₂O₅S: C, 55.99; H, 4.47; N, 6.21. Found: C, 55.65; H, 4.65; N,5.92.

EXAMPLE 463(R)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared by the method described in Example 462,substituting (R)-(−)-methyl 3-hydroxy-2-methylpropionate in place of(S)-(+)-methyl 3-hydroxy-2-methylpropionate (yield: 65 mg, 61%). ¹H NMR(300 MHz, DMSO-d₆) δ 0.75 (d, J=7 Hz, 3H), 1.81 (sextet, J=7 Hz, 1H),3.21 (t, J=6 Hz, 2H), 3.30 (s, 3H), 4.29 (dd, J=6 Hz and 12 Hz, 1H),4.40 (dd, J=6 Hz, 12 Hz, 1H), 4.49 (t, J=6 Hz, 1H), 7.52 (m, 1H), 7.61(m, 1H), 7.80 (m, 1H), 7.91 (d, J=9 Hz, 2H), 8.07 (d, J=9 Hz, 2H), 8.20(s, 1H); MS (APCI+) m/z 451 (M+H)⁺; (APCI−), m/z 485 (M+Cl)⁻. Anal.calc. for C₂₁H₂₆F₂N₂O₅S: C, 55.99; H, 4.47; N, 6.21. Found: C, 55.62; H,4.52; N, 6.06.

EXAMPLE 464(S)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

To a solution of(S)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 462B, 450 mg,˜0.9 mmol) and DBAD (207 mg, 0.9 mmol) in THF (25 mL) at −78° C. wasadded dropwise alM solution of LiHMDS (3 mL, 3 mmol) and the resultingmixture was stirred at −78° C. for 2 hours. The mixture was warmed toroom temperature and 1N NaOH (5 mL, 5 mmol) was added. After 12 hours atambient temperature, sodium acetate trihydrate (2.76 g, 20 mmol) andwater (10 mL) followed by hydroxylamine-O-sulfonic acid (2 g, 15 mmol)were added and the mixture was stirred at room temperature for 5 hours.The product was extracted with ethyl acetate and purified bychromatography (silica gel, 1:2 hexanes-EtOAc) to afford crudeintermediate (yield: 160 mg, 35%). MS (APCI+) m/z 508 (M+H)⁺; (APCI−)m/z 542 (M+Cl)⁻.

TFA (5 mL) was added to the above intermediate and the resultingsolution was left at room temperature for 24 hours. The TFA was removedin vacuo, then the residue was neutralized with saturated NaHCO₃ andextracted with ethyl acetate. The organic layer was dried over MgSO₄then filtered. The filtrate was concentrated in vacuo and the residuewas purified by column chromatography (silica gel, 1:2 hexane-ethylacetate) to provide the title compound (yield: 50 mg, 33%). ¹H NMR (300MHz, DMSO-d₆) δ 0.76 (d, J=7 Hz, 3H), 1.81 (sextet, J=7 Hz, 1H), 3.22(t, J=6 Hz, 2H), 4.28 (dd, J=6 Hz, 12 Hz, 1H), 4.40 (dd, J=6 Hz, 12 Hz,1H), 4.50 (t, J=6 Hz, 1H), 7.51 (m, 3H), 7.61 (m, 1H), 7.80 (m, 1H),7.84 (d, J=9 Hz, 2H), 7.95 (d, J=9 Hz, 2H), 8.20 (s, 1H); MS (APCI+) m/z452 (M+H)⁺; (APCI−) m/z 486 (M+Cl)⁻.

EXAMPLE 465(R)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The desired material was prepared according to the procedure of Example464 substituting(R)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinonein place of(S)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 30 mg, 20%). ¹H NMR (300 MHz, DMSO-d₆) δ 0.76 (d, J=7 Hz, 3H),1.81 (sextet, J=7 Hz, 1H), 3.22 (t, J=6 Hz, 2H), 4.28 (dd, J=6 Hz, 12Hz, 1H), 4.40 (dd, J=6 Hz and 12 Hz, 1H), 4.50 (t, J=6 Hz, 1H), 7.51 (m,3H), 7.61 (m, 1H), 7.80 (m, 1H), 7.84 (d, J=9 Hz, 2H), 7.95 (d, J=9 Hz,2H), 8.20 (s, 1H); MS (APCI+) m/z 452 (M+H)⁺; (APCI−) m/z 486 (M+Cl)⁻.Anal. calc. for C₂₀H₁₉F₂N₃O₅S: C, 53.21; H, 4.24; N, 9.30. Found: C,53.45; H, 5.53; N, 9.50.

EXAMPLE 4662-(4-Fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 178,substituting 2-methyl-1,4-butandiol in place of 2-ethyl-1-hexanol andseparating the regioisomeric products by multiple preparative thin layerchromatography runs, eluting with 4:1 ethyl acetate/hexanes (yield: 65mg, 19%). ¹H NMR (300 MHz, CDCl₃) δ 0.87 (d, J=8.1 Hz, 3H), 1.48-1.87(m, 4H), 3.13 (s, 3H), 3.41 (dd, J=6.3, 13.5 Hz, 1H), 3.46 (dd, J=6.3,13.5 Hz, 1H), 4.48-4.63 (m, 2H), 7.15-7.24 (m, 2H), 7.58-7.66 (m, 2H),7.79 (d, J=10.5 Hz, 2H), 7.91 (s, 1H), 8.07 (d, J=10.5 Hz, 2H); MS(APCI+) m/z 447 (M+H).

EXAMPLE 4672-(3,4-Difluorophenyl)-4-(3-oxo-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 460substituting 4-hydroxy-2-butanone in place of acetol. (yield: 95.0 mg,210%). mp 134-135° C.; ¹H NMR (300 MHz, CDCl₃) δ 2.06 (s, 3H), 2.81 (t,J=9 Hz, 2H), 3.13 (s, 3H), 4.75 (t, J=9 Hz, 2H), 7.30 (m, 1H), 7.45 (m,1H), 7.58 (m, 1H), 7.73 (d, J=9 Hz, 2H), 7.89 (s, 1H), 8.05 (d, J=9 Hz,2H); MS (DCI/NH₃) m/z 449 (M+H)⁺, 466 (M+NH₄)⁺. Anal. calc. forC₂₁H₁₈F₂N₂O₅S: C, 56.25; H, 4.02; N, 6.25. Found: C, 55.97; H, 4.17; N,6.11.

EXAMPLE 4682-(4-Fluorophenyl)-4-(3-oxo-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 460starting with2-(4-fluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand substituting 4-hydroxy-2-butanone in place of acetol. (yield: 85.0mg, 20%). mp 133-136° C.; ¹H NMR (300 MHz, CDCl₃) δ 2.04 (s, 3H), 2.80(t, J=9 Hz, 2H), 3.13 (s, 3H), 4.76 (t, J=9 Hz, 2H), 7.20 (t, J=9 Hz,2H), 7.55 (m, 2H), 7.75 (d, J=9 Hz, 2H), 7.91 (s, 1H), 8.05 (d, J=9 Hz,2H). MS (DCI/NH₃) m/z 431 (M+H)⁺, 448 (M+NH₄)⁺. Anal. calc. forC₂₁H₁₉FN₂O₅S: C, 58.60; H, 4.42; N, 6.52. Found: C, 58.87; H, 4.55; N,6.51.

EXAMPLE 4692-(4-Fluorophenyl)-4-(4-hydroxy-2-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 178,substituting 2-methyl-1,4-butandiol in place of 2-ethyl-1-hexanol andseparating the regioisomeric products by multiple preparative thin layerchromatography runs, eluting with 4:1 ethyl acetate/hexanes (yield: 43mg, 12%). ¹H NMR (300 MHz, CDCl₃) δ 0.87 (d, J=8.1 Hz, 3H), 1.33-1.46(m, 1H), 1.50-1.67 (m, 2H), 1.93-2.04 (m, 1H), 3.13 (s, 3H), 3.54-3.72(m, 2H), 4.29 (dd, J=−6.0, 9.3 Hz, 1H), 4.43 (dd, J=6.0, 9.3 Hz, 1H),7.15-7.24 (m, 2H), 7.58-7.66 (m, 2H), 7.79 (d, J=10.5 Hz, 2H), 7.91 (s,1H), 8.07 (d, J=10.5 Hz, 2H); MS (APCI+) m/z 447 (M+H)⁺.

EXAMPLE 4702-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 459,substituting2-(4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 600 mg, 60%). mp 163-164° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 1.05(s, 6H), 1.73 (t, J=6 Hz, 2H), 4.30 (s, 1H), 4.52 (t, J=6 Hz, 2H), 7.37(t, J=9 Hz, 1Hz, 7.47 (s, 2H), 7.65 (dd, J=9 Hz, J=3 Hz, 2H), 8.83 (d,J=9 Hz, 2H), 8.95 (d, J=9 Hz, 2H), 8.18 (s, 1H); MS (DCI/NH₃) m/z 448(M+H)⁺. Anal. calcd. for C₂₁H₂₂FN₃O₅S: C, 56.36; H, 4.95; N, 9.39.Found: C, 55.96; H, 4.89; N, 9.09.

EXAMPLE 4712-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 471A 3,4-Difluorophenylhydrazine

A stirred mixture of 3,4-difluoroaniline (12.9 g, 0.1 mol) inconcentrated hydrochloric acid (60 mL) was chilled to −10° C. with anice/methanol bath. A solution of sodium nitrite (6.9 g, 0.1 mol) inwater (30 mL) was added at a rate which maintained the temperature ofthe reaction mixture below 110° C. After stirring for 2 hours, thereaction mixture was cooled to 0° C. and a solution of tin(II) chloride(56.88 g, 0.3 mol) in concentrated hydrochloric acid (50 mL) was addeddropwise with vigorous stirring. Additional concentrated hydrochloricacid (150 mL) was added to the reaction mixture and stirring wascontinued for 2 hours. The reaction mixture was filtered to collect theprecipitated hydrochloride salt of the title compound. This precipitatewas dissolved in water (75 mL) and the resulting solution was basifiedwith 50% aqueous sodium hydroxide and extracted with ethyl acetate. Theorganic extracts were dried (Na₂SO₄) and filtered. The filtrate wasconcentrated in vacuo to provide the title intermediate as a brown oil(8.11 g, 57.4%).

EXAMPLE 471B 2-(3,4-Difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone

The title intermediate was prepared by the method of Example 194A,substituting 3,4-difluorophenylhydrazine (Example 471A) for4-fluorophenylhydrazine hydrochloride.

EXAMPLE 471C2-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-bromo-3(2H)-pyridazinone

The dibromo-intermediate from Example 471B was reacted according to theprocedure described in Example 194B, substituting3-methyl-1,3-butanediol in place of methanol, to selectively react atthe 4-position and provide the title intermediate.

EXAMPLE 471D2-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

The product from Example 471C (12.79 g, 32.86 mmol) was coupled to4-(methyl-thio)phenylboronic acid (6.07 g, 36.15 mmol) with K₂CO₃ (10 g,72.3 mmol) and PdCl₂(PPh₃)₂ (1.15 g, 1.64 mmol) in ethanol (200 mL) at60-65° C. for 40-70 minutes to provide the title intermediate (yield:9.16 g, 64.5%).

EXAMPLE 471E2-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The sulfide from Example 471D was oxidized to the title compound by themethod of Example 10 (yield: 7.46 g, 76%). m.p. 131-133° C.; ¹H NMR (300MHz, DMSO-d₆) δ 1.04 (s, 6H), 1.73 (t, J=6 Hz, 2H), 3.29 (s, 3H), 4.43(s, 1H), 4.54 (t, J=6 Hz, 2H), 7.52 (m, 1H), 7.62 (ddd, J=9 Hz, J=9 Hz,J=1.5 Hz, 1H), 7.82 (ddd, J=9 Hz, J=9 Hz, J=3 Hz, 1H), 7.91 (d, J=9 Hz,1H), 8.08 (d, J=9 Hz, 2H), 8.20 (s, 1H); MS (DCI−NH₃) m/e 465 (M+H)⁺.Anal. calcd. for C₂₂H₂₂F₂N₂O₅S: C, 56.88; H, 4.77; N, 6.03. Found: C,56.92; H, 4.88; N, 5.94.

EXAMPLE 472

s2-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 459,substituting2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 300 mg, 50%). mp 181-181° C.; ¹H NMR (300 MHz, DMSO-d₆)-81.04(s, 6H), 1.72 (t, J=6 Hz, 2H), 4.43 (s, 1H), 4.53 (t, J=6 Hz, 2H), 7.49(s, 2H), 7.53 (m, 1H), 7.63 (ddd, J=9 Hz, J=9 Hz, J=1.5 Hz, 1H), 7.79(ddd, J=9 Hz, J=9 Hz, J=3 Hz, 1H), 7.83 (d, J=9 Hz, 1H), 7.95 (d, J=9Hz, 2H), 8.19 (s, 1H); MS (DCI/NH₃) m/z 466 (M+H)⁺. Anal. calcd. forC₂₁H₂₁F₂N₂O₅S: C, 54.12; H, 4.66; N, 8.81. Found: C, 54.19; H, 4.55; N,9.03.

EXAMPLE 4732-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the sequence of reactionsdescribed in Example 471, substituting 3-chloro-4-fluorophenylhydrazinein place of 3,4-difluorophenylhydrazine (yield: 200 mg, 89%). mp108-110° C.; ¹H NMR (300 MHz, CDCl₃) δ 1.24 (s, 6H), 1.89 (t, 2H, J=6Hz), 2.34 (s, 1H), 3.12 (s, 3H), 4.57 (t, J=6 Hz, 2H), 7.25 (t, J=9 Hz,1H), 7.60 (m, 1H), 7.78 (d, J=6 Hz, 1H), 7.79 (d, J=9 Hz, 2H), 7.92 (s,1H), 8.08 (d, J=9 Hz, 2H); MS (DCI/NH₃) m/z 481 (M+H)⁺; Anal. calcd. forC₂₂H₂₂FClN₂O₅S: C, 54.94; H, 4.61; N, 5.82. Found: C, 54.87; H, 4.65; N,5.72.

EXAMPLE 4742-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 459,substituting2-(3-chloro-4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 473) in place of2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(yield: 160 mg, 45%). mp 59-62° C.; ¹H NMR (300 MHz, DMSO-d₆ δ 1.05 (s,6H), 1.73 (t, 2H, J=6 Hz), 4.32 (s, 1H), 4.54 (t, J=6 Hz, 2H), 7.50 (s,2H), 7.60 (t, J=9 Hz, 1H), 7.66 (m, 1H), 7.73 (d, J=9 Hz, 2H), 7.74 (d,J=9 Hz, 2H), 7.75 (m, 1H), 8.22 (s, 1H); MS (DCI/NH₃) m/z 482 (M+H)⁺.Anal. calcd. for C₂₁H₂₁FClN₃O₅S: C, 52.33; H, 4.39; N, 8.71. Found: C,52.30; H, 5.03; N, 8.10.

EXAMPLE 4752-(3-Chlorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the sequence of reactionsdescribed in Example 471, substituting 3-chlorophenylhydrazine in placeof 3,4-difluorophenylhydrazine (yield: 200 mg, 89%). ¹H NMR (300 MHz,CDCl₃) δ 8.04 (d, J=8.5 Hz, 2H), 7.91 (s, 1H), 7.77 (d, J=8.5 Hz, 2H),7.67 (m, 1H), 7.57 (m, 1H), 7.40 (t, J=8.8 Hz, 1H), 7.36 (m, 1H), 4.54(t, J=6.3 Hz, 2H), 3.10 (s, 3H), 2.56 (s, 1H), 1.86 (t, J=6.3 Hz, 2H),1.20 (s, 6H), MS (DCI/NH₃) m/z 462(M+H)⁺.

EXAMPLE 4762-(3-Chlorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 459,substituting2-(3-chlorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 475) in place of2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.¹H NMR (300 MHz, CDCl₃) δ 8.03 (d, J=8.7 Hz, 2H), 7.91 (s, 1H), 7.70 (d,J=8.7 Hz, 2H), 7.68 (m, 1H), 7.57 (m, 1H), 7.41 (m, 1H), 7.38 (m, 1H),5.65 (s, 2H), 4.51 (t, J=6.6 Hz, 2H), 2.70 (br s, 1H), 1.87 (t, J=6.6Hz, 2H), 1.20 (s, 6H); MS-(DCI/NH₃) m/z 463 (M+H)⁺.

EXAMPLE 4772-(4-Fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the sequence of reactionsdescribed in Example 471, substituting 4-fluorophenylhydrazine in placeof 3,4-difluorophenylhydrazine and substituting 2-methyl-1,2-propanediol(prepared by the LAH reduction of methyl 2-hydroxyisobutyrate) in placeof 3-methyl-1,3-butanediol. mp 152-154° C., ¹H NMR (300 MHz, CDCl₃) δ8.10 (d, 2H, J=18 Hz), 7.95 (s, 1H), 7.83 (d, 2H, J=18 Hz), 7.63 (d, 1H,J=18 Hz), 7.61 (d, 1H, J=18 Hz), 4.18 (s, 2H), 3.13 (s, 3H), 1.19 (s,6H), MS (DCI/NH₃) m/z 433 (M+H), 450 (M+NH₄), Analysis for C₂₁H₂₁FN₂O₅S,Calcd: C, 58.32; H, 4.89; N, 6.48. Found: C, 58.42; H, 5.05; N, 6.43.

EXAMPLE 4782-(4-Fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 459,substituting2-(4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinone(Example 477) in place of2-(3,4-difluoro-phenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.mp 155-158° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (s, 1H), 7.92 (s, 4H),7.67 (d, 1H, J=18 Hz), 7.64 (d, 1H, J=18 Hz), 7.49 (s, 2H), 7.38 (d, 1H,J=18 Hz), 7.35 (d, 1H, J=18 Hz), 4.54 (s, 1H), 4.19 (s, 2H), 1.00 (s,6H), MS (ESI+): m/z 434 (M+H), 456 (M+Na)⁺, 889 (2M+Na)⁺; Analysis forC₂₀H₂₀FN₃O₅S, Calcd: C, 55.42; H, 4.65; N, 9.69. Found: C, 55.64; H,4.85; N, 9.53.

EXAMPLE 4792-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the sequence of reactionsdescribed in Example 471, substituting 3-chloro-4-fluorophenylhydrazinein place of 3,4-difluorophenylhydrazine and substituting2-methyl-1,2-propanediol (prepared by the LAH reduction of methyl2-hydroxyisobutyrate) in place of 3-methyl-1,3-butanediol. mp 122-124°C., ¹H NMR (300 MHz, CDCl₃) δ 0.98 (s, 6H), 3.29 (s, 3H), 4.21 (s, 2H),4.56 (s, 1H), 7.61 (dd, 1H, J=7.17 Hz), 7.67 (ddd, 1H, J=2.7 Hz), 7.93(dd, 1H, J=2.7 Hz), 7.98 (d, 2H, J=8 Hz), 8.06 (d, 2H, J=8 Hz), 8.22 (s,1H); MS (DCI/NH₃) m/z 465(M−H)-Anal. Calcd for C₂₁H₂₀ClFN₂O₅S: C, 54.02;H, 4.32; N, 6.00. Found: C 54.06, H4.57, N 5.95.

EXAMPLE 4802-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 459,substituting2-(3-chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 479) in place of2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.mp 176-178° C., ¹H NMR (300 MHz, CDCl₃) δ 1.00 (s, 6H), 4.19 (s, 2H),4.54 (s, 1H), 7.49 (s, 2H), 7.62 (t, 1H, J=9 Hz), 7.66 (ddd, 1H, J=25.9Hz), 7.92 (s, 4.5H), 7.94 (d, 0.5H, J=2 Hz), 8.20 (s, 1H); MS (DCI/NH₃)m/z 468 (M+H)⁺; 1 Cl, 490 (M+Na)⁺; 1 Cl; Anal. Calcd for C₂₀H₁₉ClFN₂O₅S:C, 51.34; H, 4.09; N, 8.98. Found: C, 51.33; H, 4.23; N, 8.76.

EXAMPLE 4812-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the sequence of reactionsdescribed in Example 471, substituting 3-chlorophenylhydrazine in placeof 3,4-difluorophenylhydrazine and substituting 2-methyl-1,2-propanediol(prepared by the LAH reduction of methyl 2-hydroxyisobutyrate) in placeof 3-methyl-1,3-butanediol. ¹H NMR (300 MHz, CDCl₃) δ 8.15 (m, 2H), 7.98(s, 1H), 7.85 (m, 2H), 7.76 (m, 1H), 7.62 (m, 1H), 7.43 (m, 2H), 4.22(s, 2H), 3.15 (s, 3H), 1.21 (s, 6H); MS (DCI/NH₃) m/z 449 (M+H)⁺; Anal.Calcd for C₂₁H₂₁ClN₂O₅S: C, 56.18; H, 4.72; N, 6.24. Found: C 56.08, H4.67, N 6.23.

EXAMPLE 4822-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 459,substituting2-(3-chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 481) in place of2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (s, 1H), 7.93 (m, 4H), 7.75 (m, 1H),7.61-7.48 (m, 5H), 4.53 (s, 2H), 4.20 (s, 3H), 1.00 (s, 6H); MS (ESI−)m/z 448 (M−H)⁻; Anal. Calcd for C₂₀H₂₀H₂₀ClN₃O₅S: C, 53.39; H, 4.48; N,9.34. Found: C 53.11, H 4.82, N 9.24.

EXAMPLE 4832-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the sequence of reactionsdescribed in Example 471, substituting 2,2,2-trifluoroethylhydrazine inplace of 3,4-difluorophenylhydrazine and substituting2-methyl-1,2-propanediol (prepared by the LAH reduction of methyl2-hydroxyisobutyrate) in place of 3-methyl-1,3-butanediol. ¹H NMR (300MHz, CDCl₃) δ 1.18 (s, 6H), 2.62 (br s, 1H), 3.15 (s, 3H), 4.20 (s, 2H),4.85 (q, J=9 Hz, 2H), 7.78 (d, J=9 Hz, 2H), 7.85 (s, 1H), 8.08 (d, J=9Hz, 2H); MS (DCI/NH₃) m/z 421 (M+1)⁺; Analysis calculated forC₁₇H₁₉F₃N₂O₅S: C, 48.57; H, 4.56; N, 6.66. Found: C, 48.72; H, 4.78; N,6.56.

EXAMPLE 4842-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared by the following sequence of reactions.Mucobromic acid and 2,2,2-trifluoroethylhydrazine hydrochloride werereacted to provide2-(2,2,2-trifluoroethyl)-4,5-dibromo-3(2H)-pyridazinone following theprocedure in Example 194A. The dibromo-intermediate was reactedaccording to the procedure described in Example 194B, substituting2-methyl-1,2-propanediol in place of methanol, to selectively react atthe 4-position and provide2-(2,2,2-trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-bromo-3(2H)-pyridazinone.This 5-bromo-compound was coupled to4-[2-(tetrahydropyranyl)thio]phenylboronic acid (prepared fromTHP-protected 4-bromothiophenol and triisopropyl borate) with K₂CO₃ andPdCl₂(PPh₃)₂ in ethanol at 60-65° C. for 40-70 minutes to provide2-(2,2,2-trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-[2-(tetrahydropyranyl)thio]phenyl]-3(2H)-pyridazinone.This intermediate THP-sulfide was then converted to the title compoundby treatment with N-chloro-succinimide (3.5 equivalents) at −0° C. inTHF/H₂O for 15 minutes to an hour followed by addition of excessammonium hydroxide at 0° C. and stirring at ambient temperature for 3hours. Aqueous work-up and column chromatographic purification (80:20pentane/ethyl acetate) provided the title compound. ¹H NMR (300 MHz,CDCl₃) δ 1.18 (s, 6H), 2.65 (br s, 1H), 4.15 (s, 2H), 4.85 (q, J=9 Hz,2H), 4.9 (s, 2H), 7.75 (d, J=9 Hz, 2H), 7.85 (s, 1H), 8.05 (d, J=9 Hz,2H); MS (DCI/NH₃) m/z 422 (M+H)⁺; Analysis calculated for C₁₆H₁₈F₃N₃O₅S:C, 45.60; H, 4.30; N, 9.97. Found: C, 45.86; H, 4.63; N, 9.81.

EXAMPLE 4852-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example483, substituting neopentyl glycol in place of 2-methyl-1,2-propanediol.

EXAMPLE 4862-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example484, substituting neopentyl glycol in place of 2-methyl-1,2-propanediol.

EXAMPLE 4872-(4-Fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example459, substituting2-(4-fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 466) for2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

EXAMPLE 4882-(3,4-Difluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the sequence ofreactions described in Example 471, substituting 2-methyl-1,4-butanediolfor 3-methyl-1,3-butanediol, then separating the regioisomeric productsby multiple preparative thin layer chromatography runs.

EXAMPLE 4892-(3-Chloro-4-fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the sequence ofreactions described in Example 471, substituting3-chloro-4-fluorophenylhydrazine for 3,4-difluorophenylhydrazine andsubstituting 2-methyl-1,4-butanediol for 3-methyl-1,3-butanediol, thenseparating the regioisomeric products by multiple preparative thin layerchromatography runs.

EXAMPLE 4902-(3-Chlorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the sequence ofreactions described in Example 471, substituting 3-chlorophenylhydrazinefor 3,4-difluorophenylhydrazine and substituting 2-methyl-1,4-butanediolfor 3-methyl-1,3-butanediol, then separating the regioisomeric productsby multiple preparative thin layer chromatography runs.

EXAMPLE 4912-(3,4-Difluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example459, substituting2-(3,4-difluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 488) for2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

EXAMPLE 4922-(3-Chloro-4-fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example459, substituting2-(3-chloro-4-fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 489) for2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

EXAMPLE 4932-(3-Chlorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example459, substituting 2-(3-chlorophenyl)-4(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 490) for2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

EXAMPLE 494(S)-2-(4-Fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example464, substituting(S)-2-(4-fluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonefor(S)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

EXAMPLE 495(R)-2-(4-Fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example465, substituting(R)-2-(4-fluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonefor(R)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

EXAMPLE 496(S)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example462, substituting2-(3-chloro-4-fluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl-3(2H)-pyridazinone.

EXAMPLE 497(S)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound can be prepared according to the method of Example464, substituting(S)-2-(3-chloro-4-fluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of (S)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

EXAMPLE 498(R)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example463, substituting2-(3-chloro-4-fluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl-3(2H)-pyridazinone.

EXAMPLE 499(R)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example464, substituting(R)-2-(3-chloro-4-fluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of(S)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

EXAMPLE 500(S)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example462, substituting2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-0.331pyridazinone in place of2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl-3(2H)-pyridazinone.

EXAMPLE 501(S)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example464, substituting(S)-2-(3-chlorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of(S)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

EXAMPLE 502(R)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound can be prepared according to the method of Example463, substituting2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

EXAMPLE 503(R)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound can be prepared according to the method of Example464, substituting(R)-2-(3-chlorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of(S)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

EXAMPLE 504(S)-2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example462, substituting2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl-3(2H)-pyridazinone.

EXAMPLE 505(S)-2-(2,22-Trifluoroethyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example484, substituting (R)-3-t-butoxy-2-methyl-1-propanol (Example 462A) inplace of 2-methyl-1,2-propanediol. After Suzuki coupling with4-[2-(tetrahydropyranyl)thio]phenylboronic acid, the resultingintermediate is treated with NCS and NH₄OH as in Example 484. Thissulfonamide product is then treated with TFA (as in Example 462C) tocleave the t-butyl ether and provide the title compound.

EXAMPLE 506(R)-2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example463, substituting2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl-3(2H)-pyridazinone.

EXAMPLE 507(R)-2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example505, substituting (S)-3-t-butoxy-2-methyl-1-propanol in place of(R)-3-t-butoxy-2-methyl-1-propanol.

EXAMPLE 5082-(4-Fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the sequence ofreactions described in Example 471, substituting 4-fluorophenylhydrazinein place of 3,4-difluorophenylhydrazine and substituting neopentylglycol in place of 3-methyl-1,3-butanediol.

EXAMPLE 5092-(4-Fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example459, substituting2-(4-fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonefor2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

EXAMPLE 5102-(3,4-Difluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the sequence of reactionsdescribed in Example 471, substituting neopentyl glycol in place of3-methyl-1,3-butanediol (yield: 300 mg, 71%). mp 161-162° C.; ¹H NMR(300 MHz, DMSO-d₆) δ 0.72 (s, 6H), 3.05 (d, J=6 Hz, 2H), 3.30 (s, 3H),4.19 (s, 2H), 4.54 (t, J=6 Hz, 1H), 7.52 (m, 1H), 7.62 (dd, J=9 Hz, J=9Hz, 1H), 7.82 (ddd, J=9 Hz, J=9 Hz, J=3 Hz, 1H), 7.92 (d, J=9 Hz, 1H),8.08 (d, J=9 Hz, 2H), 8.21 (s, 1H); MS (DCI/NH₃) m/z 465 (M+H); Anal.calcd. for C₂₂H₂₂F₂N₂O₅S: C, 56.88; H, 4.77; N, 6.03. Found: C, 56.84;H, 4.83; N, 5.99.

EXAMPLE 5112-(3,4-Difluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(aminosulfonyl)-phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example459, substituting2-(3,4-difluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonefor2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

EXAMPLE 5122-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the sequence ofreactions described in Example 471, substituting3-chloro-4-fluorophenylhydrazine in place of 3,4-difluorophenylhydrazineand substituting neopentyl glycol in place of 3-methyl-1,3-butanediol.

EXAMPLE 5132-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(amino-sulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example459, substituting2-(3-chloro-4-fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonefor2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

EXAMPLE 5142-(3-Chlorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the sequence ofreactions described in Example 471, substituting 3-chlorophenylhydrazinein place of 3,4-difluorophenylhydrazine and substituting neopentylglycol in place of 3-methyl-1,3-butanediol.

EXAMPLE 5152-(3-Chlorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the method of Example459, substituting2-(3-chlorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinonefor2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

EXAMPLE 516N-[[4-[2-(3,4-Difluorophenyl)-4-(2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide

A mixture of2-(3,4-difluorophenyl)-4-(2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone(Example 403, 1 equivalent), acetic anhydride (3 equivalents),4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2equivalents) is stirred at room temperature for 16 hours. The reactionmixture is partitioned between ethyl acetate and water. The organiclayer is washed with brine then dried over MgSO₄ and filtered. Thefiltrate is concentrated in vacuo to give the title compound.

EXAMPLE 517N-[[4-[2-(3,4-Difluorophenyl)-4-(2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]-sulfonyl]acetamidesodium salt

To a suspension ofN—[[4-[2-(3,4-Difluorophenyl)-4-(2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide(Example 516, 1 equivalent) in absolute ethanol is added a solution ofsodium hydroxide (1 equivalent) in absolute ethanol. The mixture isstirred at room temperature for 10 minutes and concentrated in vacuo.The residue is dried at high vacuum to provide the title compound.

EXAMPLE 518N-[[4-[2-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-2H-pyridazin-3-on-5yl]-phenyl]sulfonyl]acetamide

A mixture of2-(4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone(Example 470, 1 equivalent), acetic anhydride (3 equivalents),4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2equivalents) is stirred at room temperature for 16 hours. The reactionmixture is partitioned between ethyl acetate and water. The organiclayer is washed with brine then dried over MgSO₄ and filtered. Thefiltrate is concentrated in vacuo to give the title compound.

EXAMPLE 519N-[[4-[2-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide,sodium salt

To a suspension ofN—[[4-[2-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide(Example 518, 1 equivalent) in absolute ethanol is added a solution ofsodium hydroxide (1 equivalent) in absolute ethanol. The mixture isstirred at room temperature for 10 minutes and concentrated in vacuo.The residue is dried at high vacuum to provide the title compound.

EXAMPLE 520N-[[4-[2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide

A mixture of2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone(Example 459, 1 equivalent), acetic anhydride (3 equivalents),4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2equivalents) is stirred at room temperature for 16 hours. The reactionmixture is partitioned between ethyl acetate and water. The organiclayer is washed with brine then dried over MgSO₄ and filtered. Thefiltrate is concentrated in vacuo to give the title compound.

EXAMPLE 521N-[[4-[2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide,sodium salt

To a suspension ofN—[[4-[2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide(Example 520, 1 equivalent) in absolute ethanol is added a solution ofsodium hydroxide (1 equivalent) in absolute ethanol. The mixture isstirred at room temperature for 10 minutes and concentrated in vacuo.The residue is dried at high vacuum to provide the title compound.

EXAMPLE 522N-[[4-[2-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide

A mixture of2-(3-chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone(Example 480, 1 equivalent), acetic anhydride (3 equivalents),4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2equivalents) is stirred at room temperature for 16 hours. The reactionmixture is partitioned between ethyl acetate and water. The organiclayer is washed with brine then dried over MgSO₄ and filtered. Thefiltrate is concentrated in vacuo to give the title compound.

EXAMPLE 523N-[[4-[2-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide,sodium salt

To a suspension ofN—[[4-[2-(3-chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide(Example 522, 1 equivalent) in absolute ethanol is added a solution ofsodium hydroxide (1 equivalent) in absolute ethanol. The mixture isstirred at room temperature for 10 minutes and concentrated in vacuo.The residue is dried at high vacuum to provide the title compound.

EXAMPLE 524N-[[4-[2-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide

A mixture of2-(3-chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(amino-sulfonyl)phenyl]-3(2H)-pyridazinone(Example 482, 1 equivalent), acetic anhydride (3 equivalents),4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2equivalents) is stirred at room temperature for 16 hours. The reactionmixture is partitioned between ethyl acetate and water. The organiclayer is washed with brine then dried over MgSO₄ and filtered. Thefiltrate is concentrated in vacuo to give the title compound.

EXAMPLE 525N-[[4-[2-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide,sodium salt

To a suspension ofN—[[4-[2-(3-chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide(Example 525, 1 equivalent) in absolute ethanol is added a solution ofsodium hydroxide (1 equivalent) in absolute ethanol. The mixture isstirred at room temperature for 10 minutes and concentrated in vacuo.The residue is dried at high vacuum to provide the title compound.

EXAMPLE 526N-[[4-[2-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5yl]-phenyl]sulfonyl]acetamide

A mixture of2-(2,2,2-trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone(Example 484, 1 equivalent), acetic anhydride (3 equivalents),4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2equivalents) is stirred at room temperature for 16 hours. The reactionmixture is partitioned between ethyl acetate and water. The organiclayer is washed with brine then dried over MgSO₄ and filtered. Thefiltrate is concentrated in vacuo to give the title compound.

EXAMPLE 527N-[[4-[2-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-yl]phenyl]sulfonyl]acetamide,sodium salt

To a suspension ofN—[[4-[2-(2,2,2-trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide(Example 526, 1 equivalent) in absolute ethanol is added a solution ofsodium hydroxide (1 equivalent) in absolute ethanol. The mixture isstirred at room temperature for 10 minutes and concentrated in vacuo.The residue is dried at high vacuum to provide the title compound.

EXAMPLE 528N-[[4-[2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide

A mixture of2-(2,2,2-trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone(Example 486, 1 equivalent), acetic anhydride (3 equivalents),4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2equivalents) is stirred at room temperature for 16 hours. The reactionmixture is partitioned between ethyl acetate and water. The organiclayer is washed with brine then dried over MgSO₄ and filtered. Thefiltrate is concentrated in vacuo to give the title compound.

EXAMPLE 529N-[[4-[2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide,sodium salt

To a suspension ofN—[[4-[2-(2,2,2-trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide(Example 528, 1 equivalent) in absolute ethanol is added a solution ofsodium hydroxide (1 equivalent) in absolute ethanol. The mixture isstirred at room temperature for 10 minutes and concentrated in vacuo.The residue is dried at high vacuum to provide the title compound.

EXAMPLE 5302-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the sequence of reactionsdescribed in Example 471, substituting 2,2,2-trifluoroethylhydrazine inplace of 3,4-difluorophenylhydrazine. ¹H NMR (300 MHz, CDCl₃) δ 1.25 (s,6H), 1.88 (t, 2H, J=9 Hz), 2.35 (br s, 1H), 3.15 (s, 3H), 4.55 (t, 2H,J=7.5 Hz), 4.85 (q, 2H, J=9 Hz), 7.75 (d, 2H J=9 Hz), 7.65 (s, 1H), 8.05(d, 2H J=9 Hz); MS (DCI/NH₃) m/z 435 (M+H)⁺; Analysis calculated forC₁₈H₂₁F₃N₂O₅S: C, 49.77; H, 4.87; N, 6.45. Found: C, 49.71; H, 4.90; N,6.45.

EXAMPLE 5312-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 484,substituting 3-methyl-1,3-butanediol in place of2-methyl-1,2-propanediol. ¹H NMR (300 MHz, CDCl₃) δ 1.85 (t, 2H, J=6Hz), 2.78 (s, 6H), 4.55 (t, 2H, J=6 Hz), 4.85 (q, 2H, J=9 Hz), 5.3 (s,2H), 7.68 (d, 2H J=9 Hz), 7.85 (s, 1H), 8.05 (d, 2H J=9 Hz), 8.45 (br s,1H); MS (DCI/NH₃) m/z 436 (M+H)⁺; Analysis calculated for C₁₇H₂₀F₃N₃O₅S:C, 46.89; H, 4.62; N, 9.65. Found: C, 47.18; H, 4.93; N, 9.86.

EXAMPLE 5322-(3,4-Dichlorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the sequence of reactionsdescribed in Example 471, substituting 3,4-dichlorophenylhydrazine inplace of 3,4-difluorophenylhydrazine. mp 118-120° C.; ¹H NMR (300 MHz,CDCl₃) δ 1.25 (s, 6H), 1.92 (t, J=6 Hz, 2H), 3.13 (s, 3H), 4.07 (t, J=6Hz, 2H), 7.58 (d, J=9 Hz, 1H), 7.59 (dd, J=9 Hz, J=2 Hz, 1H), 7.80 (d,J=9 Hz, 2H), 7.87 (d, J=2 Hz, 1H), 7.84 (s, 1H), 8.19 (d, J=9 Hz, 2H);MS (DCI/NH₃) m/z 497 (M+H)⁺. Anal. calcd. for C₂₂H₂₂Cl₂N₂O₅S: C, 53.12;H, 4.45; N, 5.63. Found: C, 52.80; H, 4.53; N, 5.35.

EXAMPLE 5332-[(3-Trifluoromethyl)phenyl]-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the sequence of reactionsdescribed in Example 471, substituting3-(trifluoromethyl)phenylhydrazine in place of3,4-difluorophenylhydrazine and substituting 2-methyl-1,2-propanediol(prepared by the LAH reduction of methyl 2-hydroxyisobutyrate) in placeof 3-methyl-1,3-butanediol (yield: 200 mg, 75%). mp 143-144° C.; ¹H NMR(300 MHz, CDCl₃) δ 1.20 (s, 6H), 3.13 (s, 3H), 4.11 (s, 2H), 7.64 (m,2H), 7.84 (d, J=9 Hz, 2H), 7.90 (d, J=9 Hz, 1H), 7.97 (d, J=9 Hz, 1H),7.98 (s, 1H), 8.13 (d, J=9 Hz, 2H); MS (DCI/NH₃) m/z 483 (M+H)⁺; Anal.calcd. for C₂₂H₂₁F₃N₂O₅S 0.5 C₄H₁₀O₂: C, 54.75; H, 4.79; N, 5.32. found:C, 55.15; H, 4.77; N, 5.09.

EXAMPLE 5342-(3,4-Dichlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the sequence of reactionsdescribed in Example 471, substituting 3,4-dichlorophenylhydrazine inplace of 3,4-difluorophenylhydrazine and substituting2-methyl-1,2-propanediol (prepared by the LAH reduction of methyl2-hydroxyisobutyrate) in place of 3-methyl-1,3-butanediol (yield: 1.7 g,75%). mp 108-110° C.; ¹H NMR (300 MHz, DMSO-d₆) δ0.96 (s, 6H), 3.38 (s,3H), 4.20 (s, 2H), 4.52 (s, 1H), 7.68 (dd, J=9 Hz, J=3 Hz, 1H), 7.83 (d,J=9 Hz, 1H), 7.78 (d, J=9 Hz, 2H), 7.79 (d, J=3 Hz, 1H), 8.04 (d, J=9Hz, 2H), 8.22 (s, 1H); MS (DCI/NH₃) m/z 483 (M+H); Anal. calcd. forC₂₁H₂₀Cl₂N₂O₅S: C, 52.18; H, 4.17; N, 5.79. Found: C, 52.41; H, 4.22; N,5.53.

EXAMPLE 535(R,S)-2-(4-Fluorophenyl)-4-(3-hydroxy-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared by reacting the product from Example468,2-(4-fluorophenyl)-4-(3-oxo-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(20 mg, 0.05 mmol) in methanol (5 mL) at 0° C. with sodium borohydride(4 mg, 0.1 mmol). The reaction mixture was allowed to warm to roomtemperature, then volatile components were removed under reducedpressure. The residue was treated with water and 10% aqueous citric acidsolution was added to bring the pH to 7. The resulting precipitate wascollected by filtration and dried to provide the title compound as anoff-white solid (11 mg, 50.9%). mp 63-66° C.; ¹H NMR (300 MHz, CDCl₃) δ1.21 (d, J=6 Hz, 3H), 1.60-1.73 (m, 1H), 1.84-1.96 (m, 1H), 3.14 (s,3H), 4.01-4.14 (m, 1H), 4.20-4.28 (m, 1H), 4.64 (dt, J=3 Hz, J=9 Hz,1H), 7.20 (t, J=9 Hz, 2H), 7.43-7.55 (m, 2H), 7.81 (d, J=9 Hz, 2H), 7.96(s, 1H), 8.10 (d, J=9 Hz, 2H); MS (DCI/NH₃)-m/z 433 (M+H)⁺.

EXAMPLE 5362-(3,4-Difluorophenyl)-4-(1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 536A2-(3,4-Difluorophenyl)-4-(1-butoxy)-5-chloro-3(2H)-pyridazinone

To a stirred, room temperature solution of n-butanol (0.81 g, 10.93mmol, 1.1 equiv.) in THF (20 mL) was slowly added 1.0 M sodiumbis(trimethylsilyl)amide in THF (12 mL, 12 mmol, 1.2 equiv.). Thereaction mixture was stirred for 0.5 hours, then it was transferred to asolution of 2-(3,4-difluorophenyl)-4,5-dichloro-3(2H)-pyridazinone (2.88g, 10.4 mmol, 1.0 equiv.) in THF (80 mL). The resulting reaction mixturewas stirred for 0.5 hours at room temperature to provide the titlecompound (2.5 g, 79.4%).

EXAMPLE 536B2-(3,4-Difluorophenyl)-4-(1-butoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

A slurry of palladium(II) acetate (9.0 mg, 0.04 mmol),triphenylphosphine (21.0 mg, 0.08 mmol) and isopropanol (1 mL) wasstirred at room temperature for 10 minutes. To this mixture was added2-(3,4-Difluorophenyl)-4-(1-butoxy)-5-chloro-3(2H)-pyridazinone (Example536A, 0.63 g, 2 mmol), 4-(methylthio)benzeneboronic acid (0.403 mg, 2.4mmol) and isopropanol (4 mL). A solution of K₃PO₄ (0.66 g, 3 mmol) inwater (1 mL) was also added and the resulting reaction mixture wasdeoxygenated by bubbling nitrogen through it for 2 minutes. The reactionmixture was then stirred under a nitrogen atmosphere for 15 hours at 70°C. The reaction mixture was then cooled to room temperature and water(15 mL) was added to provide a precipitate. The precipitate wascollected by filtration and rinsed with water then hexane to give afterdrying the title compound (0.77 g, 95%).

EXAMPLE 536C2-(3,4-Difluorophenyl)-4-(1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

To a solution of2-(3,4-difluorophenyl)-4-(1-butoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(Example 536B, 0.6 g, 1.5 mmol) in acetone (10 m at −20° C. was slowlyadded over 5 minutes a 32% solution of peracetic acid in acetic acid(3.75 mmol). The reaction mixture was allowed to warm to roomtemperature at which point water (30 mL) was added. Stirring wascontinued for 0.5 hours, then the precipitate was collected byfiltration and washed with water to provide the title compound (0.61 g,94%). mp 129-132° C.; ¹H NMR (300 MHz, CDCl₃) δ 0.88 (t, J=6 Hz, 3H),1.20-1.36 (m, 2H), 1.54-1.68 (m, 2H), 3.14 (s, 3H), 4.52 (t, J=6 Hz,2H), 7.25-7.34 (m, 1H), 7.44-7.50 (m, 1H), 7.55-7.62 (m, 2H), 7.77-7.82(m, 2H), 7.92 (s, 1H), 8.05-8.10 (m, 2H); MS (DCI/NH₃) m/z 435 (M+H);Anal. calcd. for C₂₁H₂₀F₂N₂O₄S: C, 58.06; H, 4.64; N, 6.44. Found: C,57.82; H, 4.53; N, 6.31.

EXAMPLE 5372-(3-Chloro-4-fluorophenyl)-4-(2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 536substituting 2-methyl-1-propanol in place of n-butanol and substituting2-(3-chloro-4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone for2-(3,4-difluorophenyl)-4,5-dichloro-3(2H)-pyridazinone in Example 536A.The resulting intermediate was subjected to the conditions in Example536B, substituting the catalyst PdCl₂(PPh₃)₂ in place of thepalladium(II) acetate-triphenylphosphine slurry. The resultingintermediate was then oxidized by the method of Example 536C to providethe title compound (0.58 g, 92%). mp 116-120° C.; ¹H NMR (300 MHz,CDCl₃) δ 0.86 (d, J=6 Hz, 6H), 1.85-1.94 (m, 1H), 3.14 (s, 3H), 4.32 (d,J=6 Hz, 2H), 7.24-7.30 (m, 1H), 7.56-7.62 (m, 1H), 7.77-7.83 (m, 3H),7.86 (m, 1H), 7.92 (s, 1H), 8.05-8.10 (m, 2H); MS (DCI/NH₃) m/z 451(M+H)⁺; Anal. calcd. for C₂₁H₂₀ClFN₂O₄S: C, 55.94; H, 4.47; N, 6.21.Found: C, 55.81; H, 4.38; N, 6.18.

EXAMPLE 5382-(3-Chloro-4-fluorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 536substituting 3-methyl-1-butanol in place of n-butanol to provide thetitle compound (0.62 g, 92%). mp 148-152° C.; ¹H NMR (300 MHz, CDCl₃) δ0.86 (d, J=6 Hz, 6H), 1.50-1.70 (m, 3H), 3.14 (s, 3H), 4.54 (t, J=6 Hz,2H), 7.24-7.30 (m, 1H), 7.56-7.62 (m, 1H), 7.77-7.83 (m, 3H), 7.86 (m,1H), 7.92 (s, 1H), 8.05-8.10 (m, 2H); MS (DCI/NH3) m/z 465 (M+H); Anal.calcd. for C₂₂H₂₂ClFN₂O₄S: C, 56.83; H, 4.77; N, 6.02. Found: C, 56.70;H, 4.77; N, 6.11.

EXAMPLE 5392-(3,4-Dichlorophenyl)-4-(2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 536substituting 2-methyl-1-propanol in place of n-butanol and substituting2-(3,4-dichlorophenyl)-4,5-dibromo-3(2H)-pyridazinone for2-(3,4-difluorophenyl)-4,5-dichloro-3(2H)-pyridazinone to provide thetitle compound (0.63 g, 98%). mp 127-129° C.; ¹H NMR (300 MHz, CDCl₃) δ0.86 (d, J=6 Hz, 6H), 1.82-1.94 (m, 1H), 3.14 (s, 3H), 4.30 (d, J=6 Hz,2H), 7.56-7.62 (m, 2H), 7.77-7.82 (m, 2H), 7.86 (m, 1H), 7.92 (s, 1H),8.06-8.10 (m, 2H); MS (DCI/NH₃) m/z 467 (M+H); Anal. calcd. forC₂₁H₂₀Cl₂N₂O₄S: C, 53.97; H, 4.31; N, 5.99. Found: C, 53.82; H, 4.29; N,5.89.

EXAMPLE 5402-(3,4-Dichlorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 536substituting 3-methyl-1-butanol in place of n-butanol to provide thetitle compound (0.63 g, 98%). mp 130-134° C.; ¹H NMR (300 MHz, CDCl₃) δ0.86 (d, J=6 Hz, 6H), 1.50-1.68 (m, 3H), 3.14 (s, 3H), 4.51 (t, J=6 Hz,2H), 7.56-7.62 (m, 2H), 7.77-7.82 (m, 2H), 7.86 (m, 1H), 7.92 (s, 1H),8.06-8.10 (m, 2H); MS (DCI/NH₃) m/z 481 (M+H)⁺; Anal. calcd. forC₂₂H₂₂Cl₂N₂O₄S: C, 54.89; H, 4.61; N, 5.82. Found: C, 54.72; H, 4.56; N,5.73.

EXAMPLE 5412-(3,4-Difluorophenyl)-4-(4-hydroxy-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 536substituting 1,4-butanediol in place of n-butanol and substituting2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone for2-(3,4-difluorophenyl)-4,5-dichloro-3(2H)-pyridazinone to provide thetitle compound (0.61 g, 95%). mp 110-113° C.; ¹H NMR (300 MHz, CDCl₃) δ1.52-1.60 (m, 2H), 1.72-1.82 (m, 2H), 3.15 (s, 3H), 3.62 (t, J=6 Hz,2H), 4.52 (t, J=6 Hz, 2H), 7.25-7.34 (m, 1H), 7.44-7.50 (m, 1H),7.55-7.62 (m, 1H), 7.77-7.82 (m, 2H), 7.92 (s, 1H), 8.05-8.10 (m, 2H);MS (DCI/NH₃) m/z 468 (M+H); Anal. calcd. for C₂₁H₂₀F₂N₂O₅S: C., 55.99;H, 4.48; N, 6.22. Found: C, 55.79; H, 4.41; N, 5.96.

EXAMPLE 5422-[3-(Trifluoromethyl)phenyl]-4-(2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 536substituting 2-methylpropanol for n-butanol and substituting2-[3-(trifluoromethyl)phenyl]-4,5-dibromo-3(2H)-pyridazinone in place of2-(3,4-difluorophenyl)-4,5-dichloro-3(2H)-pyridazinone to provide thetitle compound (0.58 g, 90%). mp 125-127° C.; ¹H NMR (300 MHz, CDCl₃) δ0.84 (d, J=6 Hz, 6H), 1.86-1.98 (m, 1H), 3.14 (s, 3H), 4.30 (d, J=6 Hz,2H), 7.60-7.70 (m, 2H), 7.79-7.84 (m, 2H), 7.94 (s, 1H), 7.88-7.98 (m,2H), 8.06-8.12 (m, 2H); MS (DCI/NH₃) m/z 484 (M+H); Anal. calcd. forC₂₂H₂₁F₃N₂O₄S: C, 56.65; H, 4.54; N, 6.00. Found: C, 56.49; H, 4.56; N,5.81.

EXAMPLE 5432-[3-(Trifluoromethyl)phenyl]-4-(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 536substituting 3-methyl-1-butanol in place of n-butanol and substituting2-[3-(trifluoromethyl)phenyl]-4,5-dibromo-3(2H)-pyridazinone in place of2-(3,4-difluorophenyl)-4,5-dichloro-3(2H)-pyridazinone to provide thetitle compound (0.53 g, 74%). mp 82-85° C.; ¹H NMR (300 MHz, CDCl₃) δ0.95 (d, J=6 Hz, 6H), 1.52-1.64 (m, 3H), 3.14 (s, 3H), 4.52 (d, J=6 Hz,2H), 7.60-7.70 (m, 2H), 7.79-7.84 (m, 2H), 7.94 (s, 1H), 7.88-7.98 (m,2H), 8.06-8.12 (m, 2H); MS (DCI/NH₃) m/z 498 (M+H); Anal. calcd. forC₂₃H₂₃F₃N₂O₄S: C, 57.49; H, 4.82; N, 5.83. Found: C, 57.47; H, 4.94; N,5.60.

EXAMPLE 5442-[3-(Trifluoromethyl)phenyl]-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 536substituting 3-methyl-1,3-butanediol in place of n-butanol andsubstituting2-[3-(trifluoromethyl)phenyl]-4,5-dibromo-3(2H)-pyridazinone in place of2-(3,4-difluorophenyl)-4,5-dichloro-3(2H)-pyridazinone to provide thetitle compound (1.2 g, 75%). mp 90-93° C.; ¹H NMR (300 MHz, CDCl₃) δ1.14 (s, 6H), 1.90 (t, J=6 Hz, 2H), 3.14 (s, 3H), 4.58 (t, J=6 Hz, 2H),7.60-7.70 (m, 2H), 7.79-7.84 (m, 2H), 7.94 (s, 1H), 7.88-7.98 (m, 2H),8.06-8.12 (m, 2H); MS (DCI/NH₃) m/z 514 (M+H)⁺; Anal. calcd. forC₂₃H₂₃F₃N₂O₅S: C, 55.64; H, 4.67; N, 5.64. Found: C, 56.01; H, 4.83; N,5.06.

EXAMPLE 545(R)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 545A

Ethyl (R)-3-(tert-butyldimethylsiloxy)butanoate

To a stirred, room temperature solution of ethyl (R)-3-hydroxybutanoate(5.00 g, 37.8 mmol) and tert-butyldimethylsilyl chloride (6.85 g, 45.5mmol) in DMF (90 mL) was added imidazole (3.87 g, 56.9 mmol). Thisreaction mixture was stirred at room temperature for 18 hours. Thereaction mixture was partitioned between hexane (300 mL) and water (100mL). The organic layer was washed with water (2×100 mL) then dried(MgSO₄) and filtered. The filtrate was concentrated under reducedpressure to give the title compound.

EXAMPLE 545B (R)-3-(tert-Butyldimethylsiloxy)-1-butanol

The crude product from Example 545A (˜37 mmol) was dissolved indichloromethane (100 mL). To this stirred solution, chilled to −78° C.,was added dropwise a 1M solution of diisobutylaluminum hydride indichloromethane (185 mL, 185 mmol). The reaction mixture was stirred at−78° C. for two hours, then it was allowed to warm to −30° C. andstirred an additional 0.5 hours. Methanol was then added carefully at−20° C. to quench any remaining hydride. The reaction mixture was thendiluted with methyl tert-butylether (200 mL) and washed with aqueoussodium tartrate solution (4×100 mL) and brine (2×100 mL). The organiclayer was dried (MgSO₄) and filtered. The filtrate was concentratedunder reduced pressure to give the crude title compound (6.3 g, 83%).

EXAMPLE 545C(R)-2-(3,4-Difluorophenyl)-4-[3-(tert-butyldimethylsiloxy)-1-butoxy]-5-bromo-3(2H)-pyridazinone

To a stirred, 0° C. solution of the product from Example 545B (3.4 g, 10mmol) in THF (20 mL) was added 1M sodium bis(trimethylsilyl)amide in THF(12 mL, 12 mmol). The reaction mixture was stirred at room temperaturefor 0.5 hours, then it was transferred to a stirred, −30° C. solution of2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone (3.66 g, 10 mmol)in THF (100 mL). The reaction mixture was stirred at −30° C. for 1 hour,then overnight while warming to room temperature. The reaction wasquenched with saturated aqueous ammonium chloride solution (100 mL) andextracted with ethyl acetate (2×100 mL). The organic layer was washedwith brine (2×20 mL), then dried (MgSO₄), and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bycolumn chromatography (silica gel, 90:10 hexane/ethyl acetate) toprovide the title intermediate (2.5 g, 51%).

EXAMPLE 545D(R)-2-(3,4-Difluorophenyl)-4-[3-(tert-butyldimethylsiloxy)-1-butoxy]-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

Under a nitrogen atmosphere, a mixture of the product from Example 545C(0.98 g, 2 mmol), 4-(methylthio)benzeneboronic acid (0.4 g, 2.4 mmol),K₃PO₄ (1.2 g, 6 mmol), PdCl₂(PPh₃)₂ (28 mg, 0.04 mmol), isopropanol (9mL), and water (1 mL) was stirred at 70° C. for 4 hours. The reactionmixture was then cooled to room temperature, water (30 mL) was added andstirring was continued for 2 hours. The crude black precipitate wascollected by filtration then washed with water (10 mL) and hexane (10mL). This title intermediate was used without further purification inthe following oxidation/deprotection step.

EXAMPLE 545E(R)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A stirred solution of the product from step Example 545D(˜2 mmol) inacetone (10 mL) was chilled to 0° C. To this was added 32% peraceticacid in acetic acid solution (1.42 mL, 6 mmol). The reaction mixture wasstirred for 1 hour while warming to room temperature. At this point theoxidation was complete, but some of the product's hydroxy group wasstill silylated so 1M tetrabutylammonium fluoride in THF (4 mL, 4 mmol)was added and stirring was continued for 0.5 hours. The reaction mixturewas then treated with 5% aqueous sodium thiosulfate solution (30 mL) for2 hours. The precipitated product was collected by filtration, washedwith water (10 mL) and hexane (10 mL). The solid was stirred inisopropanol (5 mL) for 6 hours then collected by filtration and dried toprovide the title compound (0.78 g, 87%). mp 126-129° C.; ¹H NMR (300MHz, CDCl₃) δ 1.22 (d, J=6 Hz, 3H), 1.62-1.74 (m, 1H), 1.84-1.94 (m,1H), 3.16 (s, 3H), 3.30 (s br, 1H), 4.00-4.10 (m, 1H), 4.20-4.30 (m,1H), 4.63 (td, J=9.6 Hz, J=4 Hz, 1H), 7.25-7.34 (m, 1H), 7.46-7.52 (m,1H), 7.56-7.64 (m, 1H), 7.78-7.84 (m, 2H), 7.97 (s, 1H), 8.06-8.12 (m,2H); MS (DCI/NH₃) m/z 468 (M+NH₄)⁺.

EXAMPLE 546 (S)-2-(3,4-Difluorophenyl)-4-(3hydroxy-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method of Example 545substituting ethyl (S)-3-hydroxybutanoate in place of ethyl(R)-3-hydroxybutanoate (0.72 g, 80%). mp 128-130° C.; ¹H NMR (300 MHz,CDCl₃) δ 1.22 (d, J=6 Hz, 3H), 1.62-1.74 (m, 1H), 1.84-1.94 (m, 1H),3.16 (s, 3H), 3.30 (s br, 1H), 4.00-4.10 (m, 1H), 4.20-4.30 (m, 1H),4.63 (td, J=9.6 Hz, J=4 Hz, 1H), 7.25-7.34 (m, 1H), 7.46-7.52 (m, 1H),7.56-7.64 (m, 1H), 7.78-7.84 (m, 2H), 7.97 (s, 1H), 8.06-8.12 (m, 2H);MS (DCI/NH₃) m/z 468 (M+NH₄)⁺.

EXAMPLE 547(S)-2-(3,4-Difluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneEXAMPLE 547A Methyl (S)-2-hydroxy-3-methylbutanoate

The title compound (CAS Registry # [17392-84-6]) is prepared byliterature procedures (e.g. Journal of Organic Chemistry, (1994) 59(7),1933-1936).

EXAMPLE 547B Methyl (S)-2-(tert-butyldimethylsiloxy)-3-methylbutanoate

The title compound is prepared by the method of Example 545A,substituting methyl (S)-2-hydroxy-3-methylbutanoate (Example 547A) inplace of ethyl (R)-3-hydroxybutanoate.

EXAMPLE 547C (S)-2-(tert-Butyldimethylsiloxy)-3-methyl-1-butanol

The title compound is prepared by the method of Example 545B,substituting methyl (S)-2-(tert-butoxydimethylsiloxy)-3-methylbutanoate(Example 547B) in place of ethyl(R)-3-(tert-butyldimethylsiloxy)butanoate (Example 545A).

EXAMPLE 547D(S)-2-(3,4-Difluorophenyl)-4-[2-(tert-butyldimethylsiloxy)-3-methyl-1-butoxy]-5-bromo-3(2H)-pyridazinone

The title compound is prepared by the method of Example 545C,substituting (S)-2-tert-butyldimethylsiloxy-3-methyl-1-butanol (Example547C) in place of (R)-3-(tert-butyldimethylsiloxy)-1-butanol (Example545B).

EXAMPLE 547E2-(3,4-Difluorophenyl)-4-[(S)-2-(tert-butyldimethylsiloxy)-3-methyl-1-butoxy]-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

The title intermediate is prepared by the method of Example 545D,substituting(S)-2-(3,4′-difluorophenyl)-4-[2-(tert-butyldimethylsiloxy)-3-methyl-1-butoxy]-5-bromo-3(2H)-pyridazinone(Example 547D) in place of(R)-2-(3,4-difluorophenyl)-4-[3-(tert-butyldimethylsiloxy)-1-butoxy]-5-bromo-3(2H)-pyridazinone(Example 545C).

EXAMPLE 547F(S)-2-(3,4-Difluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound is prepared by the method of Example 545E,substituting(S)-2-(3,4-difluorophenyl)-4-[2-(tert-butyldimethylsiloxy)-3-methyl-1-butoxy]-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(Example 547E) in place of(R)-2-(3,4-difluorophenyl)-4-[3-(tert-butyldimethylsiloxy)-1-butoxy]-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone(Example 545D).

EXAMPLES 548-558

The following compounds may be prepared according to the sequence ofreactions described in Example 547, substituting the appropriate2-(X-phenyl)-4,5-dibromo-3(2H)-pyridazinone in place of2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone.

Example Number X 548 4-F 549 4-Cl 550 3-F 551 3-Cl 552 3-Br 553 3-CF₃554 3-Cl-4-F 555 4-Cl-3-F 556 3,4-di-Cl 557 4-F-3-CF₃ 558 3-Br-4-F

EXAMPLE 559(R)-2-(3,4-Difluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the sequence ofreactions described in Example 547, substituting methyl(R)-2-hydroxy-3-methyl-butanoate [17392-84-6] prepared as described in(Tetrahedron, 1995, 51(38), 10513-10522) in place of methyl(S)-2-hydroxy-3-methylbutanoate.

EXAMPLES 560-570

The following compounds can be prepared according to the sequence ofreactions described in Example 559, substituting the appropriate2-(X-phenyl)-4,5-dibromo-3(2H)-pyridazinone in place of2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone.

Example Number X 560 4-F 561 4-Cl 562 3-F 563 3-Cl 564 3-Br 565 3-CF₃566 3-Cl-4-F 567 4-Cl-3-F 568 3,4-di-Cl 569 4-F-3-CF₃ 570 3-Br-4-F

EXAMPLE 5712-(3,4-Difluoro-phenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the sequence ofreactions described in Example 547, substituting methyl(R)-2,3-dihydroxy-3-methylbutanoate [37504-90-8] (Australian Journal ofChemistry, (1986) 39(11), 1907-1909) in place of methyl(S)-2-hydroxy-3-methylbutanoate.

EXAMPLES 572-582

The following compounds may be prepared according to the sequence ofreactions described in Example 571, substituting the appropriate2-(X-phenyl)-4,5-dibromo-3(2H)-pyridazinone in place of2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone.

Example Number X 572 4-F 573 4-Cl 574 3-F 575 3-Cl 576 3-Br 577 3-CF₃578 3-Cl-4-F 579 4-Cl-3-F 580 3,4-di-Cl 581 4-F-3-CF₃ 582 3-Br-4-F

EXAMPLE 5832-(3,4-Difluorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the sequence ofreactions described in Example 547, substituting methyl(S)-2,3-dihydroxy-3-methylbutanoate [75347-92-1] (Journal of OrganicChemistry, 1980, 45(25), 5218-5220) in place of methyl(S)-2-hydroxy-3-methylbutanoate.

EXAMPLES 584-594

The following compounds may be prepared according to the sequence ofreactions described in Example 571, substituting the appropriate2-(X-phenyl)-4,5-dibromo-3(2H)-pyridazinone in place of2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone.

Example Number X 584 4-F 585 4-Cl 586 3-F 587 3-Cl 588 3-Br 589 3-CF₃590 3-Cl-4-F 591 4-Cl-3-F 592 3,4-di-Cl 593 4-F-3-CF₃ 594 3-Br-4-F

EXAMPLE 5952-(3,4-Difluorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the sequence ofreactions described in Example 471, substituting4-methyl-1,4-pentanediol [1462-10-8] (Journal of Organic Chemistry,(1972) 37, 3310-3322) in place of methyl 3-methyl-1,3-butanediol.

EXAMPLE 596-606

The following compounds may be prepared according to the sequence ofreactions described in Example 471, substituting4-methyl-1,4-pentanediol [1462-10-8] (Journal of Organic Chemistry,(1972) 37, 3310-3322) in place of methyl 3-methyl-1,3-butanediol andsubstituting the appropriate 2-(X-phenyl)-4,5-dibromo-3(2H)-pyridazinonein place of 2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone.

Example Number X 596 4-F 597 4-Cl 598 3-F 599 3-Cl 600 3-Br 601 3-CF₃602 3-Cl-4-F 603 4-Cl-3-F 604 3,4-di-Cl 605 4-F-3-CF₃ 606 3-Br-4-F

EXAMPLE 6072-(3,4-Difluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared by a carbodiimide-mediated coupling(method described in Angew. Chem., Int. Ed. Engl., (1979) 18(9), 686) of2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 471) with an N-protected-glycine (such as N-Fmoc-glycine);followed by an amino group deprotection step (such as treatment at roomtemperature with tetrabutylammonium fluoride in DMF).

EXAMPLES 608-618

The following compounds may be prepared by the method of Example 607,substituting the appropriate2-(X-phenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 471).

Example Number X 608 4-F 609 4-Cl 610 3-F 611 3-Cl 612 3-Br 613 3-CF₃614 3-Cl-4-F 615 4-Cl-3-F 616 3,4-di-Cl 617 4-F-3-CF₃ 618 3-Br-4-F

EXAMPLE 6192-(3,4-Difluorophenyl)-4-[3-{[2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared in a manner similar to that describedin J. Chem. Soc., Chem. Commun., (1993) 410-412, reacting2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 471) with an appropriately protected L-tartaric acid diester(such as below), followed by deprotection.

EXAMPLE 619A dibenzyl(2R,3R)-2,3-bis{[tert-butyl(diphenyl)silyl]oxyl}butenedioate

The alcohol groups of (+)-dibenzyl-L-tartrate can be protected as thetert-butyldiphenylsilyl ethers by standard methods as described in(Greene, T W, Wuts, P G M; Protective Groups in Organic Synthesis;3^(rd) Edition; 1999; John Wiley & Sons, Inc.; NY, N.Y.; 141-144) toprovide the title intermediate.

EXAMPLE 619B (2R,3R)-2,3-bis{[tert-butyl(diphenyl)silyl]oxy}butenedioicacid

The dibenzyl ester of Example 619A can be cleaved by standardhydrogenolysis procedures as described in (Greene, T W, Wuts, P G M;Protective Groups in Organic Synthesis; 3rd Edition; 1999; John Wiley &Sons, Inc.; NY, N.Y.; 415-419) to provide the title intermediate.

EXAMPLE 619C(3R,4R)-3,4-bis{[tert-butyl(diphenyl)silyl]oxy}dihydro-2,5-furandione

Example 619B may be reacted by standard methods as described in (Journalof Organic Chemistry, (1987) 52(3), 455-457) with trifluoroaceticanhydride to provide the title intermediate.

EXAMPLE 619D(2R,3R)-2,3-bis{[tert-butyl(diphenyl)silyl]oxy}-4-methoxy-4-oxobutanoicacid

Example 619C may be reacted with anhydrous methanol by standard methodsas described in (Organic Syntheses, Collective Volume III, (1955)169-171) to provide the title intermediate.

EXAMPLE 619E 1-isopropenyl 4-methyl(2R,3R)-2,3-bis{[tert-butyl(diphenyl)silyl]oxy}butanedioate

Example 619D may be reacted with isopropenyl acetate in the presence ofcatalytic boron trifluoride etherate and mercury(II) acetate asdescribed in (J. Chem. Soc., Chem. Commun., (1993) 410-412) to providethe title intermediate.

EXAMPLE 619F2-(3,4-Difluorophenyl)-4-{3-[((2R,3R)-2,3-bis{[tert-butyl(diphenyl)silyl]oxy}-4-methoxy-4-oxobutanoyl)oxy]-3-methylbutoxy}-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

Example 619E may be coupled to2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 471) in the presence of catalytic 4-toluene sulfonic acid bythe method described in (J. Chem. Soc., Chem. Commun., (1993) 410-412)to provide the title intermediate.

EXAMPLE 619G2-(3,4-Difluorophenyl)-4-[3-{[2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

Example 619F can be treated with aqueous sodium hydroxide in methanol asdescribed in (J. Chem. Soc., Chem. Commun., (1993) 410-412) to providethe title compound.

EXAMPLE 620-630

The following compound may be prepared by the method of Example 619F,substituting the appropriate2-(X-phenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 471), followed by treatment with aqueous sodium hydroxide inmethanol as in Example 619G.

Example Number X 620 4-F 621 4-Cl 622 3-F 623 3-Cl 624 3-Br 625 3-CF₃626 3-Cl-4-F 627 4-Cl-3-F 628 3,4-di-Cl 629 4-F-3-CF₃ 630 3-Br-4-F

EXAMPLE 6313-({2-(3,4-difluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyldihydrogen phosphate

The title compound may be prepared as described in (Kosolapoff, G M andMaier, L, Organic Phosphorus Compounds, (1973) Volume 6, John Wiley &Sons, NY, N.Y.); such as reacting2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 471) with 2-cyanoethylphosphate (Fieser, L F and Fieser, M,Reagents for Organic Synthesis, 1967, Volume 1, 172-173, John Wiley &Sons, NY, N.Y.) in the presence of DCC and pyridine. Mild alkalinehydrolysis of the cyanoethyl ester selectively provides the titlecompound.

EXAMPLE 632-642

The following compounds may be prepared by the method of Example 631,substituting the appropriate2-(X-phenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinonein place of2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[47(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 471).

Example Number X 632 4-F 633 4-Cl 634 3-F 635 3-Cl 636 3-Br 637 3-CF₃638 3-Cl-4-F 639 4-Cl-3-F 640 3,4-di-Cl 641 4-F-3-CF₃ 642 3-Br-4-F

EXAMPLE 6432-(tert-Butyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared according to the sequence ofreactions described in Example 471, substituting2-tert-butyl-4,5-dichloro-3(2H)-pyridazinone (Example 330A) in place of2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone.

EXAMPLE 6442-(tert-Butyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound may be prepared by the method of Example 607,substituting2-(tert-butyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 643) in place of2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone(Example 471).

EXAMPLE 6452-(tert-Butyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone

The title compound may be prepared by the method of Example 619,substituting2-(tert-butyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone(Example 643) in place of2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone(Example 471).

EXAMPLE 6463-({2-(tert-Butyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyldihydrogen phosphate

The title compound may be prepared by the method of Example 631,substituting2-(tert-butyl)-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone(Example 643) in place of2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone(Example 471).

Prostaglandin Inhibition Determination Compound Preparations andAdministration

For oral administration, test compounds were suspended on the day of usein 100% polyethyleneglycol (PEG 400) with a motorized homogenizerequipped with a Teflon-coated pestle (TRI-R Instrument, Jamaica, N.Y.).

To compare the mean responses of the treatment groups, analysis ofvariance was applied. Percent inhibition values were determined bycomparing the individual treatment mean values to the mean of thecontrol group. Linear regression was used to estimate IC₅₀'s/ED₅₀'s inappropriate assays.

EIA Determination of Prostaglandins

EIA reagents for prostaglandin determination were purchased fromPerceptive Diagnostics, (Cambridge, Mass.). Prostaglandin E₂ (PGE₂)levels in lavage fluids were determined after the samples were driedunder nitrogen and reconstituted with assay buffer. PGE₂ levels inenzyme assays or cell culture media were measured against standardsprepared in the same milieu. The immunoassays were conducted asrecommended by the manufacturer. The EIA was conducted in 96 wellmicrotiter plates (Nunc Roskilde, Denmark) and optical density wasmeasured using a microplate reader (Vmax, Molecular Devices Corp., MenloPark, Calif.).

Recombinant Human PGHS-1 and PGHS-2 Enzyme Assays

Inhibition of prostaglandin biosynthesis in vitro was evaluated usingrecombinant human Cox-1 (r-hu Cox1) and Cox-2 (r-hu Cox-2) enzymeassays. Representative compounds dissolved in DMSO (3.3% v/v) werepreincubated with microsomes from recombinant human PGHS-1 or PGHS-2expressed in the baculovirus/Sf9 cell system (Gierse, J. K., Hauser, S.D., Creely, D. P., Koboldt, C., Rangwala, S., H., Isakson, P. C., andSeibert, K. Expression and selective inhibition of the constitutive andinducible forms of cyclooxygenase, Biochem J. 1995, 305: 479.), togetherwith the cofactors phenol (2 mM) and hematin (1 μM) for 60 minutes priorto the addition of 10 μM arachidonic acid. The reaction was allowed torun for 2.5 minutes at room temperature prior to quenching with HCl andneutralization with NaOH. PGE₂ production in the presence and absence ofthe drug was determined by EIA analysis. The EIA was conducted in 96well microtiter plates (Nunc Roskilde, Denmark) and optical density wasmeasured using a microplate reader (Vmax, Molecular Devices Corp., MenloPark, Calif.). EIA reagents for prostaglandin determination werepurchased from Perceptive Diagnostics (Cambridge, Mass.). PGE₂ levelswere measured against standards prepared in the same milieu. Theimmunoassays were conducted as recommended by the manufacturer.

The data illustrating the inhibition of prostaglandin biosynthesis invitro by compounds of this invention is shown in Table 1. The compoundsare designated by the Example Number. Column 2 shows Cox-1 percentinhibition at the particular micromolar dose level and Column 3 showsCox-2 percent inhibition at the particular nanomolar dose level. Valuesfor Cox-1 and Cox-2 inhibition that are parenthetical indicate IC₅₀values.

TABLE 1 RHUCX1 RHUCX2 Example % Inh. at % Inh. at Number Dose (μM) Dose(μM) 10 2 @ 100 (0.014) 12 0 @ 100 97 @ 10  77 @ 1    9 @ 0.1 20 10 @100  86 @ 0.1  9 @ 0.01 21 19 @ 100  (0.92)  22 25 @ 100   91 @ 0.03  35@ 0.01 23 0 @ 100 68 @ 0.1  27 @ 0.01 24 60 @ 100  99 @ 1   0 @ 10  61 @0.1  45 @ 0.01 25 1 @ 100 93 @ 1   66 @ 0.1 26 10 @ 100  91 @ 1   44 @0.1  44 @ 0.01 32 20 @ 100  96 @ 1   83 @ 0.1 34 16 @ 100  (0.92)  35 34@ 100  (0.017) 36 21 @ 10  (0.57)  39 0 @ 100 (0.44)  40 76 @ 10  97 @1   69 @ 1   89 @ 0.1 41 13 @ 100  49 @ 1   17 @ 0.1 42 0 @ 100 99 @ 1  92 @ 0.1 43 8 @ 100 100 @ 1   96 @ 0.1 45 5 @ 100 85 @ 1   63 @ 0.1 48 0@ 100 73 @ 1    2 @ 0.1 50 23 @ 100  99 @ 1   59 @ 0.1 52 32 @ 10  99 @1   83 @ 0.1 53 10 @ 100  99 @ 1   77 @ 0.1 54 0 @ 100 95 @ 1   58 @ 0.158 0 @ 100 (0.95)  60 7 @ 100  100 @ 1,000 62 6 @ 100 (0.624) 64 68 @1   34 @ 1   36 @ 0.1 65 13 @ 100  98 @ 1   65 @ 0.1 68 32 @ 100 (0.297) 69 2 @ 100 88 @ 1   29 @ 0.1  30 @ 0.01 72 0 @ 100 65 @ 1   18 @0.1 73 9 @ 100 (1.34)  74 11 @ 100  86 @ 1   75 @ 0.1 77 35 @ 100  82 @10  39 @ 1   80 41 @ 10  (0.064) 37 @ 1   81 6 @ 100 97 @ 1   44 @ 0.184 49 @ 10  87 @ 0.3 9 @ 1  88 0 @ 100  97 @ 1,000 35 @ 0.1 89 62 @ 30 (0.35)  40 @ 10  97 35 @ 100  (0.332) 100 62 @ 10  100 @ 10   65 @ 1  61 @ 0.1 105 85 @ 1   98 @ 1   52 @ 0.1 106 19 @ 200  (0.135) 107 88 @10  86 @ 1   50 @ 1   36 @ 0.1 108 0 @ 100 (0.279) 109 6 @ 100 (0.147)110 5 @ 100 93 @ 1   50 @ 0.1 111 13 @ 100  (0.052) 112 5 @ 100 (0.136)118 31 @ 100  72 @ 0.1  17 @ 0.01 119 (0.178) (0.027) 120 15 @ 100  97 @1   45 @ 0.1 121 0 @ 100 (0.005) 122 1 @ 100 (0.285) 124 26 @ 100 (0.044) 127 50 @ 10  74 @ 1   30 @ 1   51 @ 0.1 128 14 @ 100  (0.477)132 93 @ 1   88 @ 1   43 @ 0.1 133 23 @ 100  (0.358) 134 54 @ 100 (0.053) 35 @ 10  140 (3.06)  (0.022) 141 55 @ 100  99 @ 1   62 @ 10  95@ 0.1 142 80 @ 10  96 @ 1   53 @ 1   45 @ 0.1  32 @ 0.01 143 62 @ 100 (0.076) 43 @ 10  144 (0.058) 88 @ 1   78 @ 0.1  65 @ 0.01 145 (0.238) 86@ 0.1  56 @ 0.01 146 82 @ 10  100 @ 1   53 @ 1   73 @ 0.1 147 (0.067)100 @ 1   64 @ 0.1  0 @ 0.03 149 45 @ 10  (0.003) 40 @ 1   150 56 @ 100 100 @ 0.1  39 @ 10  153 54 @ 100  (0.062) 35 @ 10  154 (0.126) (0.018)165 0 @ 100 (1.08)  166 3 @ 100 (0.199) 168 0 @ 100 85 @ 1   93 @ 0.1171 0 @ 100 82 @ 10  74 @ 1   61 @ 0.1 178 6 @ 100  92 @ 1,000 34 @ 10 180 8 @ 100 78 @ 1   48 @ 0.1 182 (5.01)  (0.07)  183 25 @ 100  97 @ 1  51 @ 0.1 187 2 @ 100 (0.094) 188 18 @ 100  (0.526) 190 (1.88)  (0.134)194 35 @ 100  90 @ 10  73 @ 1   72 @ 0.1 198 10 @ 100  68 @ 1   23 @ 0.1207 97 @ 1   81 @ 0.1 209 0 @ 100 79 @ 1   55 @ 0.1  40 @ 0.01 213 0 @100 (0.812) 219 20 @ 100  90 @ 1   75 @ 0.1 220 51 @ 100  96 @ 1   38 @1   90 @ 0.1 226 0 @ 100 (1.09)  228 7 @ 100 (0.209) 230 4 @ 100 (0.215)231 7 @ 100 90 @ 1   68 @ 0.1 232 23 @ 100  (0.024) 234 0 @ 100 (0.328)235 22 @ 100  (0.21)  237 54 @ 10  89 @ 0.1 44 @ 1   240 14 @ 100 (0.297) 241 0 @ 100 (0.028) 245 9 @ 100 (1.38)  246 0 @ 100 (0.054) 24772 @ 10  99 @ 10  55 @ 1   71 @ 1   51 @ 0.1 248 13 @ 100  (0.08)  249 6@ 100 98 @ 1   68 @ 0.1  43 @ 0.01 252 0 @ 100 87 @ 0.1  26 @ 0.01 25377 @ 100  (0.272) 29 @ 10  254 7 @ 100 84 @ 1   48 @ 0.1 256 0 @ 100(0.134) 257 0 @ 100 (0.04)  260 8 @ 100  2 @ 10 261 0 @ 200 (0.161) 26215 @ 100  (0.432) 263 1 @ 100 85 @ 10  76 @ 1   53 @ 0.1 265 8 @ 100 53@ 10  48 @ 1   33 @ 0.1 272 0 @ 100 70 @ 1   55 @ 0.1 273 16 @ 100  54 @10  42 @ 1   278 36 @ 100  96 @ 1   91 @ 0.1 279 0 @ 100 60 @ 1   31 @0.1 281 7 @ 100 71 @ 1   52 @ 0.1  47 @ 0.01 283 0 @ 100 90 @ 10  71 @1   54 @ 0.1 287 0 @ 100 93 @ 10  79 @ 1   25 @ 0.1 314 7 @ 100 51 @ 10 4 @ 1  318 23 @ 100  97 @ 1   77 @ 0.1 321 4 @ 100 (0.192) 322 39 @ 100 (0.058) 54 @ 10  323 1 @ 100 (0.365) 325 (0.199) 330 15 @ 100  85 @ 1   72 @ 0.03  5 @ 0.01 335 5 @ 100 (0.001) 338 0 @ 100 100 @ 1   83 @ 0.1339 2 @ 100 (0.088) 344 16 @ 100  (0.897) 345 0 @ 100 (0.242) 346 14 @100  94 @ 1   76 @ 0.1  48 @ 0.01 347 11 @ 100  (0.075) 349 0 @ 100(0.086) 351 3 @ 100 91 @ 1   63 @ 0.1  42 @ 0.01 352 0 @ 100 (0.154) 3536 @ 100 (0.826) 354 0 @ 100 45 @ 10  45 @ 1   36 @ 0.1 355 0 @ 100 79 @10  66 @ 1   46 @ 0.1 358 30 @ 100  (2.45)  361 3 @ 100 (0.011) 362 1 @100 84 @ 10  49 @ 1   364 0 @ 100 86 @ 1    0 @ 0.1 366 0 @ 100 (0.03) 367 0 @ 100 (0.077) 368 13 @ 100  96 @ 1   65 @ 0.1 369 0 @ 100 70 @ 1  48 @ 0.1 370 8 @ 100 (0.048) 371 8 @ 100 (0.166) 372 0 @ 100 94 @ 10  88@ 1   59 @ 0.1 374 2 @ 100 (0.02)  375 46 @ 100  (0.18)  31 @ 10  376 12@ 100  (0.027) 381 0 @ 100 (0.188) 384 82 @ 100  99 @ 1   49 @ 10  78 @0.1 386 58 @ 100  83 @ 1   47 @ 1   63 @ 0.1  58 @ 0.01 387 57 @ 10  76@ 1   60 @ 1   65 @ 0.1  56 @ 0.01 388 74 @ 10  (0.049) 36 @ 1   390 88@ 10  99 @ 10  45 @ 1   72 @ 1   60 @ 0.1 392 56 @ 100  82 @ 0.1 35 @10   65 @ 0.01 393 15 @ 100  85 @ 1   58 @ 0.1 394 86 @ 100  94 @ 1   38@ 10  64 @ 0.1  20 @ 0.01 395 91 @ 100  93 @ 1   35 @ 10  77 @ 0.1  34 @0.01 396 22 @ 100  (0.059) 397 25 @ 100  93 @ 1   58 @ 0.1  39 @ 0.01398 26 @ 100  (0.202) 400 27 @ 100  (0.142) 401 (0.753) 96 @ 1   62 @0.1  48 @ 0.01 402 89 @ 1   (0.221) 403 (150.76)   92 @ 1   64 @ 0.1  36@ 0.01 404 77 @ 100  92 @ 0.1 47 @ 10   57 @ 0.01 405 90 @ 100  (0.198)61 @ 10  406 23 @ 100  100 @ 1   64 @ 0.1  18 @ 0.01 407 32 @ 100 (0.17)  408 0 @ 100 (0.279) 410 48 @ 100   67 @ 0.035 1 @ 10   47 @0.017 411 96 @ 10  (0.009) 81 @ 1   412 31 @ 100  (0.002) 413 0 @ 100(0.11)  414 0 @ 100 87 @ 1   76 @ 0.1 418 33 @ 100  85 @ 1   52 @ 0.1 53 @ 0.025 419 12 @ 100  (0.1)  420 29 @ 100  (0.323) 421 (0.269) 92 @1   81 @ 0.1  38 @ 0.01 422 53 @ 100  52 @ 1   82 @ 10  37 @ 0.1 76 @1   423 0 @ 100 87 @ 1   68 @ 0.1  36 @ 0.01 424 7 @ 100 75 @ 1   58 @0.1  33 @ 0.01 425 12 @ 100  69 @ 0.1  31 @ 0.01 426 1 @ 100 (0.057) 4340 @ 100 (0.081) 437 16 @ 100  (0.124) 438 0 @ 100 (0.127) 440 20 @ 100 84 @ 1   59 @ 0.1  22 @ 0.01 442 55 @ 100  90 @ 0.1  56 @ 0.01 443 35 @100  86 @ 0.1  74 @ 0.01 444 0 @ 100 83 @ 1   62 @ 0.1 14 @ 10  445(56.62)  (0.069) 446 0 @ 200 (0.373) 447 0 @ 100 90 @ 1   57 @ 0.1  35 @0.01 449 5 @ 200 (0.129) 450 29 @ 100  87 @ 1   40 @ 0.1  22 @ 0.01 45110 @ 100  (0.470) 452 14 @ 100  15 @ 1   467 4 @ 100 (1.96)  475 0 @ 100(0.71)  471 (3.68)  (0.49)  478 33 @ 100  (0.81)  528 (3.4)  (0.72) 

IL-1β Induced PGE₂ Production in WISH Cells Human amnionic WISH cellswere grown to 80% confluence in 48 well plates. Following removal of thegrowth medium and two washings with Gey's Balanced Salt Solutn, 5 ngIL-1β/ml (UBI, Lake Placid, N.Y.) was added to the cells with or withouttest compound in DMSO (0.01% v/v) in Neuman-Tytell Serumless Medium(GIBCO, Grand Island, N.Y.). Following an 18 hour incubation to allowfor the maximal induction of PGHS-2, the conditioned medium was removedand assayed for PGE₂ content by EIA analysis as described above.

Monocyte U937 (ATCC, Rockville, Md.) cells were grown in a similarfashion to the WISH cells. After incubation, the conditioned medium wasremoved and assayed for Cox-1 content by EIA analysis as describedabove.

The data illustrating the inhibition of prostaglandin biosynthesis invitro by compounds of this invention is shown in Table 2. U937 valuesindicate Cox-1 percent inhibition at the particular micromolar doselevel while parenthetical values indicate IC₅₀ values. WISH cell valuesindicate percent inhibition at the particular micromolar dose levelwhile parenthetical values indicate IC₅₀ values.

Human Whole Platelet Cyclooxygenase-1 Assay (HWCX)

Blood from normal healthy volunteers is collected into tubes containingACD (acid citrate dextrose) as the anticoagulant. This blood iscentrifuged at 175×g to prepare platelet rich plasma The platelet richplasma is then centrifuged at 100×g to pellet the white blood cells,leaving the platelets in the supernatant. The supernatant is layered ona cushion of 0.7 mL of 10% bovine serum albumin in Tyrodes solution(Gibco; Grand Island, N.Y.) and then centrifuged at 1000×g. Theresulting supernatant from this centrifugation is then removed and 11 mLof Tyrodes solution is added to the remaining pellet of platelets. Theplatelets are then aliquoted at 120 μl into a 96 well plate.Experimental compounds are added and allowed to pre-incubate for 10minutes. At the end of this pre-incubation period, the calcium ionophoreA23187 is added to a final concentration of 8.8 μM and the incubation iscontinued for ten minutes. The reaction is stopped by adding cold 6 mMEDTA, the incubation mixture is centrifuged at 220×g, and thesupernatants are then analyzed for thromboxane using a commercial kitfrom Cayman Chemical (Ann Arbor, Mich.).

TABLE 2 U937 HWPX Wish Example % Inhib. at % Inhib. at % Inhib. atNumbers Dose (μM) Dose (μM) Dose (μM) 10 (4.1) (0.014) 20 33 @ 1 (0.001)24 (0.19) (0.007) 43 86 @ 10 (0.008) 9 @ 1 53 78 @ 10 90 @ 0.1  8 @ 1 44@ 0.01 65 (0.02) 69  (1.14) (0.02) 72 (25)   (0.072) 75 84 @ 10 (0.001)0 @ 3 77 (8.8) (0.126) 85 (0.47) 86 52 @ 1   47 @ 0.01 89 (3.8) (2.1)(0.05) 100  (0.13) (0.02) 102 (0.05) 105 62 @ 1  (0.018) 106 (17.5) (0.03) 108 (8)   (0.097) 109  (2.693) (0.018) 119  (0.076) (0.001) 12074 @ 3  (0.025) 58 @ 1  121 (0.041) 123 90 @ 1  (0.001) 29 @ .1  126(0.05) 129 (0.04) 132 100 @ 0.1  36 @ 0.01 140  (0.773) (0.01) 141  56 @0.3 (0.004) 142  (7.53) (0.088) 143 (0.007) 145 72 @ 1  (0.009) 30 @ .3 146 84 @ 10 (0.044) 46 @ 3  147  84 @ 0.3 (0.029) 148  51 @ 0.3 (0.042)149 89 @ 10 (0.03) 34 @ 3  152 (0.029) 153  (2.95) (0.046) 154 81 @ .3 100 @ 0.1  48 @ .1  69 @ 0.01 160 (7.2) (0.03) 162 (0.034) 165 (1.9)(0.030) 166 (9.4) (0.02) 168 47 @ 1  (0.009) 171 90 @ 1   56 @ 0.1  187(12.6)  (0.015) 189  31 @ 100 (0.041) 190  (9.96) (0.03) 191 (0.06) 194(28.09) (0.069) 198 (0.184) 203 77 @ 1   23 @ 0.1  207 (0.068) 228(19.6)  (0.086) 241 (0.0474) 243 (0.03) 244  (3.67) (0.019) 245 (0.046)246 (0.02) 247  (7.76) (0.02) 248 82 @ 30 (0.005) 17 @ 10 252 (0.044)256 (4.7) (0.028) 261 (34)   (0.099) 271 52 @ 1   15 @ 0.1  278 (0.07)279 (0.391) 287 (0.16) 317 (0.027) 320 29 @ 3  78 @ .1  15 @ .01  321 50@ 0.01 322 (0.026) 323 57 @ 0.01 324 (0.047) 325 (2.3) (0.04) 326 (0.05)330 (16.7)  (0.005) 335 (0.023) 338 (14.93) (0.004) 339  (0.393) (0.026)343  (0.191) (0.016) 344 (0.1) 345 (0.03) 349  34 @ 100 (0.041) 352(5.5) (6.048) 358 69 @ 1   0 @ 0.1 366  (1.615) (0.002) 367 50 @ 1 (0.018)  8 @ .3 368 (13.7)  64 @ 0.03 33 @ 0.01 370 (8.4) (0.02) 375 (2.04) (0.089) 381 31 @ 30 (0.075)  91 @ 100 385  (2.18) (0.023) 388  0@ .3 (0.032) 392  (1.95) (0.02) 394 (0.019) 396 (12.7)  (0.02) 397(13.8)  (0.04) 399 82 @ 0.1  39 @ 0.03 400 (0.3) (0.026) 401  (0.32)(0.017) 403  (0.902) (0.018) 404  (0.337) 96 @ 0.1  58 @ 0.01 406 (1.61) (0.026) 408 (0.029) 410 (0.053) 414 54 @ 1   46 @ 0.1  418(14.25) (0.25) 430 34 @ 10 (0.054)  89 @ 100 442 (0.42) 445 100 @ 100(0.025) 22 @ 10 446 (24.4)  (0.02) 449 (40)   (0.089) 450 (0.05) 451(22.4)  (0.15) 452 56 @ 1   1 @ 0.1 475  50 @ 100 (0.44) 467 (0.135) 471 (0.32) (0.04) 478 (0.5) (0.108) 528 (3.5) (0.054)

Carrageenan Induced Paw Edema (CPE) in Rats

Hindpaw edema was induced in male rats as described by Winter et al.,Proc. Soc. Exp. Biol. Med., 1962, 111, 544. Briefly, male Sprague-Dawleyrats weighing between 170 and 190 g were administered test compoundsorally 1 hour prior to the subplantar injection of 0.1 ml of 1% sodiumcarrageenan (lambda carrageenan, Sigma Chemical Co., St Louis, Mo.) intothe right hindpaw. Right paw volumes (ml) were measured immediatelyfollowing injection of carrageenan for baseline volume measurementsusing a Buxco plethysmograph (Buxco Electronics, Inc., Troy, N.Y.).Three hours after the injection of carrageenan, right paws wereremeasured and paw edema calculated for each rat by subtracting the zerotime reading from the 3 hour reading. Data are reported as mean percentinhibition+/−SEM. Statistical significance of results was analyzed byDunnetts multiple comparison test where p<0.05 was consideredstatistically significant.

Rat Carrageenan Pleural Inflammation (CIP) Model

Pleural inflammation was induced in male adrenalectomized Sprague-Dawleyrats following the method of Vinegar et al., Fed. Proc. 1976, 35,2447-2456. Animals were orally dosed with experimental compounds, 30minutes prior to the intrapleural injection of 2% lambda carrageenan(Sigma Chemical Co., St. Louis Mo.). Four hours later the animals wereeuthanized and the pleural cavities lavaged with ice cold saline. Thelavage fluid was then added to two volumes of ice cold methanol (finalmethanol concentration 66%) to lyse cells and precipitate protein.Eicosanoids were determined by EIA as described above.

The data illustrating the inhibition of prostaglandin biosynthesis invivo by the compounds of this invention is shown in Table 3. Valuesreported are percent inhibition at 10 milligrams per kilogram bodyweight.

Carrageenan induced air pouch prostaglandin biosynthesis model (CAP) Airpouches are formed in the backs of male Sprague Dawley rats by injecting20 mL of sterile air on day 0. Three days later the pouch was reinflatedwith an additional 10 mL of sterile air. On day 7, 1 mL of salinecontaining 0.2% lambda carrageenan (Sigma Chemical Co.) is injected intothe pouch to induce the inflammatory reaction that is characterized bythe release of prostaglandins. Test compounds are dosed at 0.1 to 10mg/kg 30 minutes prior to carrageenan. Four hours after the carrageenaninjection the pouch is lavaged and levels of prostaglandins aredetermined by enzyme immuno-assay using commercially available kits.Percent inhibitions are calculated by comparing the response in animalswhich have received vehicle to those which received compound. Values forCox-2 inhibition that are parenthetical indicate ED₅₀ values.

The data illustrating the inhibition of prostaglandin biosynthesis invivo by the compounds of this invention is shown in Table 3. Valuesreported are percent inhibition at 10 milligrams per kilogram bodyweight for CIP and CPE tests and at 3 milligrams per kilogram bodyweight for CAP testing.

TABLE 3 CIP CPE CAP Example % Inhib. % Inhib. % Inhib. Numbers @ 10 mpk@ 10 mpk @ 3 mpk  10 44  12 42 25  34 36 31  54 31 30  58 42 14 67  6257 21  66 59 7 0  67 40 @ 3mpk  68 64 40.3  69 61 45.5 87 ED₃₀ = 5.4  72 73 46 29  74 46.5 18 34  77 51 21  80 60 28.5 91  89 68.3 45.5 94 ED₅₀= 3.4 106 47 109 13 71 112 21 42.5 119 82 27 76 120 5 11 121 19 8 123 23143 59 153 51 160 56 35 166 40 59 168 0 6 180 34.5 182 59 27 98 185 5920 53 187 51 28 30 190 60 28 71 205 54 226 21 40.5 243 7 245 47 246 48248 49 256 47 257 60 261 28 79 330 4.5 335 45 339 43 90.5 ED₅₀ = 0.58346 49.5 347 27 66.5 349 63 351/64 0 352 89 ED₅₀ = 5.0 353/63 0 361 65366 63 ED₅₀ = 1.5 367 48 375 47 77.5 ED₅₀ = 0.57 376 17 77.5 378 59384/33 51 15 51 385 65 388 28 80 390 60 391 61 392 60 394 70 395 71 39623 85 397 70 400 65 41 82.5 403 43 68.5 ED₅₀ = 0.35 405 53 406 23 66.5407 61 419 48 427 78 445 15 73 446 44 92 ED₅₀ = 0.5 449 23 76 ED₅₀ = 1.8450 86 451 ED₃₀ = 0.82 80.5 ED₅₀ = 0.7 452 71 459 45 464 70 475 33 ED₅₀= 1.4 467 ED₃₀ = 1.7 ED₅₀ = 0.4 471 41 ED₅₀ = 0.9 478 26 75 528 40 ED₅₀= 1.4

Human whole blood assays Cyclooxygenase-1

Heparin anticoagulatd blood was incubated with drugs dissolved in DMSO.The samples are incubated at 37 degrees Celsius for 4.5 hours afterwhich calcium ionophore at a final concentration of 30 μM was added andthe mixture allowed to incubate for 30 minutes. The reaction was stoppedwith the addition of EGTA and cold methanol (50% final concentration).After 18 hours at −70 degrees Celsius, the plates were centrifuged andsupernatants analyzed for TXB₂.

Cyclooxygenase-2

Heparin anticoagulated blood was incubated with drugs dissolved in DMSO.The samples are incubated at 37 degrees Celsius for 15 minutes. E. colilipopolysaccharide (LPS) 5 μg/ml was then added and the samplesincubated for 5 hours. The reaction was stopped with the addition ofEGTA and cold methanol (50% final concentration). After 18 hours at −70degrees Celsius, the plates were centrifuged and supernatants analyzedfor TXB₂.

EXAMPLE 451 Human Whole Blood Cox-1 IC₅₀=29.12 Micromolar EXAMPLE 451Human Whole Blood Cox-2 IC₅₀=0.47 Micromolar EXAMPLE 471 Human WholeBlood Cox-1=55.5% at 30 Micromolar EXAMPLE 471 Human Whole BloodCox-2=85% at 0.03 Micromolar

The 4-hydroxyalkoxy-3(2H)-pyridazinone Cox-2 inhibition and in vivoactivity has been found to be suprisingly good. In addition, whencompared to the 4-alkoxy-3(2H)-pyridazinones, the hydroxyalkoxycompounds typically possess a superior oral pharmacokinetic profile,such as better plasma half-life, plasma concentration maxima, and areaunder the curve. For example, Example 375 shows a 14 day plasmamicromolar concentration (based on 10 mg/kg dosage) of 0.0 while Example451 shows a 3.43 micromolar level. In addition, the half life of Rat IV(3 mg/kg) for Example 375 was 2.9 while Example 451 showed 5.2. The AUCvalue (micromolar/hour) for Example 375 was 1.8 while Example 451 was69.

It is anticipated that the 4-hydroxyalkoxy compounds are preferred toparent alkoxy compounds with regard to once-a-day dosing to achievepredictable exposure levels across a wide range of doses while producingan antiinflammatory effect.

Pharmaceutical Compositions

The present invention also provides pharmaceutical compositions whichcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable carriers. Thepharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers. As used herein, the term “pharmaceutically acceptable carrier”means a non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as cocoabutter and suppository waxes; oils such as peanut oil, cottonseed oil;safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols;such a propylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the procedures and judgements well known to one skilled inthe art. The pharmaceutical compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracistemally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, or as an oral or nasal spray.

The compounds of the present invention may be potentially useful in thetreatment of several illness or disease states such as inflammatorydiseases, dysmennorhea, asthma, premature labor, adhesions and inparticular pelvic adhesions, osteoporosis, and ankylosing spondolitis.Current Drugs Ltd, ID Patent Fast Alert, AG16, May 9, 1997.

The compounds of the present invention may also be potentially useful inthe treatment of cancers, and in particular, colon cancer. Proc. Natl.Acad. Sci., 94, pp. 3336-3340, 1997.

The compounds of the present invention may be useful by providing apharmaceutical composition for inhibiting prostaglandin biosynthesiscomprising a therapeutically effective amount of a compound of formula Ior a pharmaceutically acceptable salt, ester, or prodrug thereof, and apharmaceutically acceptable carrier.

In addition, the compounds of the present invention may be useful byproviding a method for inhibiting prostaglandin biosynthesis comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of formula I or a pharmaceuticallyacceptable salt, ester, or prodrug thereof.

In addition, the compounds of the present invention may be useful byproviding a method for treating pain, fever, inflammation, rheumatoidarthritis, osteoarthritis, adhesions, and cancer comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of formula I.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (such as, for example, cottonseed,groundnut, corn, germ, olive, castor, sesame oils, and the like),glycerol, tetrahydrofurfuryl alcohol, poly-ethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, such as, for example, sterile injectableaqueous or oleaginous suspensions may be formulated according to theknown art using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution, suspension or emulsion in a nontoxic parenterallyacceptable diluent or solvent, such as, for example, a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution, isotonic sodium chloridesolution, and the like. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid are used inthe preparation of injectable preparations.

The injectable formulations can be sterilized by any method known in theart, such as, for example, by filtration through a bacterial-retainingfilter, or by incorporating sterilizing agents in the form of sterilesolid compositions which can be dissolved or dispersed in sterile wateror other sterile injectable medium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulatedmatrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides) Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and thus melt inthe rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is usually mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier such as, for example, sodium citrate ordicalcium phosphate and/or a) fillers or extenders such as, for example,starches, lactose, sucrose, glucose, mannitol, and silicic acid, b)binders such as, for example, carboxymethylcellulose, alginates,gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants suchas, for example, glycerol, d) disintegrating agents such as, forexample, agar-agar, calcium carbonate, potato or tapioca starch, alginicacid, certain silicates, and sodium carbonate, e) solution retardingagents such as, for example, paraffin, f) absorption accelerators suchas, for example, quaternary ammonium compounds, g) wetting agents suchas, for example, cetyl alcohol and glycerol monostearate, h) absorbentssuch as, for example, kaolin and bentonite clay, and) lubricants suchas, for example, talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof. Inthe case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients such as, forexample, lactose or milk sugar as well as high molecular weightpolyethylene glycols and the like.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using excipients such as, forexample, lactose or milk sugar as well as high molecular weightpolyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulation art. In such soliddosage forms the active-compound may be admixed with at least one inertdiluent such as, for example, sucrose, lactose or starch. Such dosageforms may also comprise, as is normal practice, additional substancesother than inert diluents, e.g., tableting lubricants and othertableting aids such as, for example, magnesium stearate andmicrocrystalline cellulose. In the case of capsules, tablets and pills,the dosage forms may also comprise buffering agents. They may optionallycontain opacifying agents and can also be of a composition that theyrelease the active ingredient(s) only, or preferentially, in a certainpart of the intestinal tract, optionally, in a delayed manner. Examplesof embedding compositions which can be used include polymeric substancesand waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as, for example,animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth,cellulose derivatives, polyethylene glycols, silicones, bentonites,silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as, for example, lactose, talc, silicic acid,aluminum hydroxide, calcium silicates and polyamide powder, or mixturesof these substances. Sprays can additionally contain customarypropellants such as chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in a suitable medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

According to the methods of treatment of the present invention, apatient, such as a human or mammal, is treated by administering to thepatient a therapeutically effective amount of a compound of theinvention, in such amounts and for such time as is necessary to achievethe desired result. By a “therapeutically effective amount” of acompound of the invention is meant a sufficient amount of the compoundto provide the relief desired, at a reasonable benefit/risk ratioapplicable to any medical treatment. It will be understood, however,that the total daily usage of the compounds and compositions of thepresent invention will be decided by the attending physician within thescope of sound medical judgment. The specific therapeutically effectivedose level for any particular patient will depend upon a variety offactors including the disorder being treated and the severity of thedisorder; the activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed; and like factors well known in the medical arts.

The total daily dose of the compounds of this invention administered toa human or other mammal in single or in divided doses can be in amounts,for example, from 0.001 to about 1000 mg/kg body weight daily or morepreferably from about 0.1 to about 100 mg/kg body weight for oraladministration or 0.01 to about 10 mg/kg for parenteral administrationdaily. Single dose compositions may contain such amounts or submultiplesthereof to make up the daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The reagents required for the synthesis of the compounds of theinvention are readily available from a number of commercial sources suchas Aldrich Chemical Co. (Milwaukee, Wis., USA); Sigma Chemical Co. (St.Louis, Mo., USA); and Fluka Chemical Corp. (Ronkonkoma, N.Y., USA); AlfaAesar (Ward Hill, Mass. 01835-9953); Eastman Chemical Company(Rochester, N.Y. 14652-3512); Lancaster Synthesis Inc. (Windham, N.H.03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical)(New Brunswick, N.J. 08901); Pfaltz and Bauer (Waterbury, Conn. 06708).Compounds which are not commercially available can be prepared byemploying known methods from the chemical literature.

1-55. (canceled)
 56. A method for treating cancer in a patient in needthereof comprising administering a prostaglandin-inhibiting compound offormula III

or a pharmaceutically acceptable salt or ester thereof, wherein R isselected from the group consisting of a) alkyl, b) aryl, wherein thearyl is optionally substituted phenyl wherein said substituents areselected from alkyl, halogen, and haloalkyl, c) arylalkyl wherein thearyl of arylalkyl is optionally substituted phenyl wherein saidsubstituents are selected from alkyl, halogen, and haloalkyl, d)haloalkyl, and e) haloalkenyl; R¹ is hydroxyalkoxy; and R⁹ is selectedfrom the group consisting of alkyl and amino.
 57. A method according toclaim 56 wherein the compound is selected from the group consisting of2-(4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinoneand2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.